Chapter 28 — Further Reading

Natriuretic Peptides: The Heart Failure Biomarkers That Became Treatments

This chapter is unusually well served by the primary literature, because almost everything that matters here was settled by large, published, well-designed randomized trials. That is not the situation in Part III of this book, and the contrast is worth experiencing directly.

A note on how to read the trial reports below: read the endpoint definitions before you read the results. In this chapter more than any other, the design decisions — which endpoint, which comparator, which population — determine what the result can mean. Bibliographic details are given so you can locate the papers; verify them against a database rather than trusting a book's transcription.

Tier 1 — Start here

Guideline documents on heart failure diagnosis and management. The current American (AHA/ACC/HFSA) and European (ESC) heart failure guidelines are surprisingly readable in their diagnostic sections, and they show you something no individual paper does: how evidence gets converted into a recommendation, with the class and level of evidence stated explicitly. Read the natriuretic peptide diagnostic algorithm and then read the pharmacotherapy section on ARNIs. Notice that the same molecular system generates recommendations of different strength for different purposes — which is §28.4 in institutional form.

A general review of the natriuretic peptide system. Levin, Gardner, and Samson's review in the New England Journal of Medicine (1998) remains a clear introduction to the physiology, written before either the biomarker or the ARNI story had resolved — which makes it a useful record of what the field believed when the expectations in §28.4 were still open.

Practical guidance on interpreting natriuretic peptide concentrations. The Heart Failure Association of the ESC has published practical guidance on the use of natriuretic peptide measurements in clinical practice (European Journal of Heart Failure, 2019). If you want the confounder discussion from §28.3 in more depth — particularly the obesity effect and the age-stratified thresholds — this is where to find it stated carefully.

Eugene Braunwald's account of how the ARNI came to exist (Journal of the American College of Cardiology, 2015) is a short, first-person history of the path from neprilysin inhibition through the omapatrilat failure to sacubitril/valsartan. It is the best single narrative of why the combination is what it is.

Tier 2 — The primary literature

The discovery

de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. "A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats." Life Sciences, 1981. Short, direct, and one of the cleanest experiments in modern endocrinology. Read it for the control condition.

Sudoh T, Kangawa K, Minamino N, Matsuo H. "A new natriuretic peptide in porcine brain." Nature, 1988. The paper that produced the misleading "B for brain" name.

The biomarker

Maisel AS et al. "Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure." New England Journal of Medicine, 2002. The Breathing Not Properly study. Read the methods on how the reference diagnosis was adjudicated — the blinding of the adjudicators is what makes the accuracy figures believable.

Januzzi JL et al. The PRIDE study of NT-proBNP in emergency-department dyspnea (American Journal of Cardiology, 2005), which did for NT-proBNP what the above did for BNP, and which is where the age-stratified thresholds originate.

Felker GM et al. "Effect of natriuretic peptide-guided therapy on hospitalization or cardiovascular mortality in high-risk patients with heart failure and reduced ejection fraction: a randomized clinical trial." JAMA, 2017. The GUIDE-IT trial, stopped for futility. This is the fourth claim from §28.4, and the paper's discussion of why the strategy added nothing is more instructive than the result.

Ledwidge M et al. "Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial." JAMA, 2013. A fifth distinct claim about the same measurement — prevention rather than diagnosis or titration. Read it as an exercise in noticing that a new claim has been made.

Nesiritide

Publication Committee for the VMAC Investigators. "Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial." JAMA, 2002. The surrogate-and-symptom evidence base. Read it as if you were a regulator in 2001, then read the 2011 trial below and ask what you would have required.

Sackner-Bernstein JD et al. Two 2005 pooled analyses — one in JAMA on short-term mortality, one in Circulation on worsening renal function — that reopened the question. Excellent examples of hypothesis-generating re-analysis performed by people who did not run the original trials.

O'Connor CM et al. "Effect of nesiritide in patients with acute decompensated heart failure." New England Journal of Medicine, 2011. The ASCEND-HF trial. The single most important paper for this chapter. Note the co-primary endpoint structure: they retained the symptom endpoint that supported approval and added the hard endpoint that had never been tested.

Packer M et al. "Effect of ularitide on cardiovascular mortality in acute heart failure." New England Journal of Medicine, 2017. The TRUE-AHF trial — a second natriuretic peptide, improved hemodynamics, no mortality benefit. Read alongside ASCEND-HF; two independent failures of one strategy say something one failure cannot.

The indirect strategy

Packer M et al. The OVERTURE trial of omapatrilat versus enalapril in chronic heart failure (Circulation, 2002), and Kostis JB et al. on omapatrilat and angioedema in hypertension (American Journal of Hypertension, 2004). The failure that determined the architecture of the successful drug.

McMurray JJV et al. "Angiotensin–neprilysin inhibition versus enalapril in heart failure." New England Journal of Medicine, 2014. PARADIGM-HF. Read the run-in description in the methods, not just the results.

Solomon SD et al. "Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction." New England Journal of Medicine, 2019. PARAGON-HF, which did not meet its primary endpoint. Read it immediately after PARADIGM-HF. Same drug, different population, different answer — the cleanest available demonstration that a rating attaches to a claim with a population attached.

Velazquez EJ et al. "Angiotensin–neprilysin inhibition in acute decompensated heart failure." New England Journal of Medicine, 2019. PIONEER-HF, which examined in-hospital initiation and NT-proBNP response — relevant to the biomarker interaction described in §28.7.

The frontier

Armstrong PW et al. "Vericiguat in patients with heart failure and reduced ejection fraction." New England Journal of Medicine, 2020. VICTORIA. A useful exercise in reading a modest hazard ratio in a high-risk population and deciding what it is worth.

Savarirayan R et al. The randomized, double-blind, placebo-controlled phase 3 trial of vosoritide in children with achondroplasia (The Lancet, 2020). Read the primary endpoint definition carefully, then ask yourself what claim the trial actually established and what claim you were tempted to infer.

Tier 3 — Deeper and more technical

Potter LR, Abbey-Hosch S, Dickey DM. "Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions." Endocrine Reviews, 2006. The receptor biology in full — particulate versus soluble guanylyl cyclases, NPR-C trafficking, and the downstream protein kinase G pathway. This is the reference for §28.2 and for understanding precisely why vericiguat is adjacent to rather than downstream of natriuretic peptide signaling.

Reviews of neprilysin substrate specificity. Worth seeking out if the §28.6 argument interests you, because the substrate list is the whole argument. The comparative kinetics — in particular the observation that BNP is a relatively poor neprilysin substrate compared with ANP and CNP — is the detail that undermines the popular shorthand describing ARNIs as "BNP boosters."

Literature on natriuretic peptide resistance in heart failure. Receptor downregulation, altered processing of proBNP with accumulation of incompletely processed and glycosylated forms, and increased clearance. This is where the §28.2 paradox is worked out properly, and it is the strongest available mechanistic account of why supplying more peptide from outside might have been unlikely to help.

Methodological literature on trials stopped early for benefit. There is a well-developed statistical literature showing that trials truncated at an interim analysis for efficacy tend, as a class, to overestimate treatment effects — the magnitude of the overestimate depending on the number of events accrued at the stopping point. Read some of it and then reconsider the PARADIGM-HF effect size. It does not change the direction of the finding. It should slightly change your point estimate.

Regulatory documents. Review packages and label histories for the drugs in this chapter are public. They show what the regulator saw, what it was uncertain about, and what post-marketing commitments it imposed — including, for the ARNI, the contraindication and washout language whose origin is the omapatrilat program.

If you only do one thing

Read ASCEND-HF and PARADIGM-HF back to back, in that order, and write down — before you read either results section — what endpoint each trial chose and why.

Two trials, one physiological system, opposite conclusions. Nothing about the underlying biology differs between them. What differs is the strategy (supply versus preserve), the setting (acute versus chronic), the comparator (placebo added to standard care versus an active drug with a proven mortality benefit), and the duration (30 days versus years).

If you can articulate, after that exercise, why the second trial succeeded where the first failed — and, more importantly, why nobody could have known in advance — you have the chapter. Everything else here is detail.