Andrew House, MD, Selection Committee member for the Heart and Kidney Connection Region
Editor's Note: The following "Scouting Report" will help you complete your bracket in the NephMadness Tournament. Read it carefully to make your selections, and discuss your thoughts in our Comments section. This article first appeared on the AJKD BLOG.
Meet the Competitors: Sacubitril (PARADIGM-HF) vs Tolvaptan
This is a real show stopper: two novel therapies going head to head in a grudge match. Sacubitril is a neprilysin inhibitor that is now coupled to a new partner (an ARB), hoping to shed a toxic past. The toxic past was a drug called omapatrilat, which has combined ACE and neprilysin inhibitory effects that initially showed promise in heart failure until angioedema stole the show and proved too hazardous.
The blockade of vasopressin receptors with tolvaptan continues to make appearances as a potential therapy in multiple arenas. How will tolvaptan hold up to an old renin-angiotensin system behemoth with shiny new neprilysin inhibition rims? This one will go down to the wire.
Sacubitril in HF (PARADIGM-HF)
The hype was palpable, like Kentucky in the John Calipari era. Will it be another group of "one and done's" or will this be a John Wooden UCLA dynasty?
The PARADIGM Trial was reported at the European Society of Cardiology Congress in Barcelona in 2014 and simultaneously published in NEJM. This trial tested whether a neprilysin inhibitor coupled to valsartan provided more benefit than enalapril in patients with heart failure.
First things first, what is neprilysin? And why should we block it? It is ubiquitously expressed but enriched in the renal proximal tubule, heart, lung, lymphocytes, and brain. Neprilysin is a circulating and membrane-bound metalloprotease that cleaves peptides. As such, it inactivates several peptide hormones including natriuretic peptides, vasoactive peptides (eg, endothelin 1, bradykinins, angiotensin II), neuropeptides (eg, substance P, enkephalins), and the beta-amyloid peptide amongst others. Some of these are "good" and others "bad". So, the net effect of neprilysin inhibition is difficult to predict.
The inhibition of neprilysin alone (in the form of candoxatril) was studied back in 1993 and reported in the journal Clinical Science. This showed no effect in blood pressure and a decrease in angiotensin II metabolism. That is why it is important to add neprilysin inhibition to either an ACE-inhibitor or an ARB.
The results of the PARADIGM Trial were impressive, but not without controversy. This was a double-blind trial, with 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less, receiving either LCZ696 (200 mg twice daily) or enalapril (10 mg twice daily). LCZ696 is a combination of the neprilysin inhibitor sacubitril and valsartan. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. The trial was stopped early because of an overwhelming benefit with LCZ696:
• The primary outcome had occurred in ~22% in the LCZ696 group compared with ~27% in the enalapril group
• Death from any cause occurred in ~17% receiving LCZ696 and ~20% receiving enalapril
• As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21%
• LCZ696 decreased the symptoms and physical limitations of heart failure.
In regard to side effects, the LCZ696 group had higher proportions of patients with hypotension and non-serious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
These results were viewed by the cardiovascular community with great enthusiasm. However, questions remain about why enalapril was used as the comparator and not valsartan.
But what about kidney disease? Well, as mentioned previously, neprilysin is highly expressed in the proximal tubule of the nephron. Hence, there is much interest in using inhibitors of neprilysin in CKD.
A rat model of diabetes showed substantial improvement in both proteinuria and kidney damage with the use of omapatrilat compared to ACE-inhibitor use. What about human data? An analysis of patients in the PARAMOUNT trial (designed to look at heart failure with preserved ejection fraction (HFpEF) showed that treatment with LCZ696 for 36 weeks led to slightly better eGFR than valsartan. However, the LCZ696 had a small but statistically increase in urinary ACR.
The UK Heart And Renal Protection III (UK HARP-III) trial will compare LCZ696 with irbesartan in a planned 360 patients with proteinuric CKD (urine ACR > 20 mg/mmol and eGFR 20-<60 mL/min/1.73 m2). The trial will investigate the short-term safety and efficacy of LCZ696 in CKD with a primary outcome being the difference between the two arms in change in measured GFR from baseline to 6 months.
This class of medications could become a potential therapy to slow the progression of CKD. We still await definitive clinical trials. Team Sacubitril has a lot of promise and will likely make some serious noise in NephMadness.
Tolvaptan in HF
The antagonists of vasopressin (vaptans) have shown great versatility, from the treatment of hyponatremia to polycystic kidney disease to heart failure, provoking the question whether Team Tolvaptan in HF can be stopped.
Why should we block vasopressin in heart failure? Well, increases in vasopressin have been shown to play a role in mediating water retention in HF. Therefore, the interruption of inappropriate activation of vasopressin could be of therapeutic benefit. The vaptans (or small molecule antagonists to the V2 receptor) now give us the ability to treat disorders with increased vasopressin levels. Short-term treatment with vaptans leads to improved fluid balance, renal function, and electrolyte composition compared to loop diuretics.
The EVEREST trial, reported in JAMA in 2007, was a randomized, double-blind, placebo-controlled study in patients (~4100) acutely decompensated and admitted to the hospital with either tolvaptan or placebo. This is in direct contradistinction to the PARADIGM Trial in which "stable" outpatients were studied.
You have to give the authors of the EVEREST trial credit for going after an extremely difficult patient population. There have been no definitive studies that have shown benefit in acutely decompensated heart failure. Unfortunately, no difference in HF morbidity or mortality was identified. A benefit with tolvaptan was seen in day 1 dyspnea scores and body weight. There were also improved serum sodium concentrations in patients with hyponatremia. However, these effects did not translate to hard outcomes.
So, where do we stand? ClinicalTrials.org lists several trials in both acute and chronic HF. Maybe vasopressin antagonism therapy needs to be given chronically and not acutely to be effective in HF.
NKF © 2015
The National Kidney Foundation
Cite this: Andrew House, Andrew Malone, Matthew Sparks. NephMadness 2015: Cardio-Nephrology Region - Medscape - Mar 02, 2015.
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