Patients with chronic kidney disease (CKD) have a high risk of cardiovascular events to the point that CKD is being included as a cardiovascular risk factor per se.1 The situation is more severe in advanced CKD; studies in large populations have shown that the worse the impairment in glomerular filtration, the more likely to suffer cardiovascular events.2

In addition, heart failure (HF) is a clinical situation that is accompanied by high morbidity and mortality. Different factors, including acute myocardial infarction or pathological dilation of the left ventricle impair cardiac function and the ejection fraction is not maintained (systolic dysfunction or HF with reduced ejection fraction) or defects of myocardial relaxation during ventricular filling (diastolic dysfunction or HF with normal ejection fraction).3

Both situations, CKD and HF, may be the cause and the consequence of each other, thus their deleterious effects are enhanced and constitute the so-called cardiorenal syndrome.4

To date, the treatment of HF had been based on the use of angiotensin-converting enzyme inhibitors in combination with beta blockers or even aldosterone antagonists. Recently, neprilysin inhibition has acquired a relevant role in the treatment of HF, by demonstrating (in combination with valsartan) its ability to decrease hospitalizations and even mortality in patients with reduced left ventricular ejection fraction (LVEF) in patients that had optimized medical treatment.5,6 Presently, the indication of sacubitrile / valsartan includes patients who with a functional class ii-iv of the New York Heart Association (NYHA) classification with optimized medical treatment and LVEF below 40 %, although the ongoing study PARAGON is designed to evaluate the efficacy of the drug in HF patients with normal ejection fraction.7

With regard to renal function, clinical trials have included patients with renal insufficiency (glomerular filtration rate [GFR] < 30mL / min / 1.73m2) although only the UK HARP-III had as its main objective the evaluate the change in GFR. In this study, there was a similar reduction in GFR and proteinuria after 12 months of follow-up with both treatment (irbesartan vs. sacubitrile/valsartan).8

Beyond clinical trials, experience with this drug in every day practice has hardly been reported. For this reason, the objective of this study is to analyze the impact of sacubitrile/valsartan in patients with CKD.

This is a retrospective cohort study including all consecutive patients who were prescribed sacubitrile/valsartan in the outpatient nephrology clinic during 2017. As Inclusion criteria: older than 18 years, with CKD stages 1–4 and with clinical criteria to receive treatment following to current recommendations.9,10 According to the guidelines at the initiation of the study, sacubitrile/valsartan was recommended to replace for angiotensin-converting enzyme inhibitors, in patients with HF with reduced ejection fraction (less than 40 %) who persisted symptomatic (NYHA class II-IV) despite receiving the optimal treatment (including beta blockers and aldosterone inhibitors at maximum tolerated doses).11 Exclusion criteria, were those derived from the contraindication of the drug prescription, hypotension defined as systolic blood pressure less than 100mmHg or serum potassium levels greater than 5.4mmol/L. The study included patients seen in 2017 and a follow-up extended for 6 months. The study was terminated on June 30, 2018.

Baseline information included: demographic data (age and sex), medical history such as hypertension (according to the definition of 8°report of the Joint National Committee12 or use of at least one antihypertensive), dyslipidemia according to the ATP III guidelines (LDL cholesterol higher than 160mg/dL in patients with 0–1 risk factor; greater than 130mg/dL in patients with more than one risk factor; greater than 100mg/dL in patients with coronary heart disease or equivalent or in treatment with hypolipidemic agents13), diabetes mellitus,14 history of cerebrovascular events, ischemic heart disease (defined as a history of acute myocardial infarction or angina) and echocardiographic parameters (LVEF [by Teichholz], pulmonary hypertension, diastolic dysfunction, defined by the quotient of the wave E / A or E / e ', if available15). The concomitant medication and its modification during patient follow-up wasalso collected.

The dose of sacubitrile/valsartan was gradually titrated. It was started with 24/26mg every 12h, then 49/51mg every 12h at the 1st month and finally, 97/103mg every 12h at 3 months, providing that it was tolerated. Patients were evaluated at the beginning of the study and in the subsequent visits at 1, 3 and 6 months of treatment. In these visits, blood and urine was collected for analytical determination to assess renal function (creatinine, estimated GFR [FGe] by CKD-EPI, albumin/creatinine ratio [ACR] in urine). Serum Sodium, potassium, uric acid and N-terminal peptide natriuretic factor (Nt-proBNP)16,17 were also determined. In addition, at 6 months, data from echocardiogram performed by protocol was collected. During the follow-up, adverse events and treatment abandonments were recorded.

The study complies with current data protection regulations, as well as ethical principles and it was approved by the Ethical Committee of the University Hospital of La Princesa. Patients expressed their consent to participate in the study.

In the present study, based on real everyday clinical practice, it is demonstrated that the use of sacubitrile/valsartan is safe in patients with CKD and generates a renal benefit in terms of progression of renal failure. As a novelty and in contrast to published studies, our study demonstrates the beneficial effect of the drug in a population of older patients with a higher percentage of diabetes.

The treatment of HF has undergone a significant change with the accessibility to sacubitrile/valsartan, initially known as LCZ696. The benefit of this molecule lies in the ability of sacubitrile to inhibit the action of neprilysin, an endopeptidase that degrades vasoactive substances such as natriuretic peptides, bradykinin or adrenomodulin.18 Although theoretically sacubitrile may reduce blood pressure and improve HF by such mechanism (especially through the inhibition of natriuretic peptides), it was necessary to associate valsartan after demonstrating that an escape in the activation of Angiotensin II secondary to the inhibition of neprilysin limited its effect, especially with regard to the effect on blood pressure.19

Results from randomized clinical trials have been able to demonstrate the superiority of sacubitrile/valsartan as compared with enalapril in reduction mortality and hospitalization due to HF with reduced LVEF. In the PARADIGM-HF study, 8442 patients were randomized to receive this drug and it was compared with enalapril in subjects with HF stages IIIV of NYHA, with systolic dysfunction despite optimized medical treatment. Patients with CKD were included, although the limit was a eGFR of 30mL/min/1.73m2. In addition to demonstrating the superiority of sacubitrile/valsartan over enalapril in cardiovascular terms, the change in renal function and the appearance of hyperkalemia were analyzed as secondary objectives; deterioration of renal function was more frequent in the enalapril group (although the definition of this event was too weak: patients that reached creatinine above 2.5mg/dL).5 In our study, we have been able to demonstrate that renal function not only remains stable but even transient improvements may occur although not clinically significant. It is likely that this was due to the drug's ability to improve the HF functional class, which allows adjustement the diuretic treatment (in our case, these were 11 patients), in addition to the positive hemodynamic effect on the glomerulus itself. In unpublished data we have been able to verify that in these patients the extracellular volume (analyzed by spectroscopic bioimpedance) improves after the initiation of the drug, allowing a fine adjustment in the dose of loop diuretics. In a post hoc analysis of the PARAMOUNT-HF study (which included patients with HF with preserved ejection fraction) it was shown that after 36 weeks of treatment, sacubitrile/valsartan improved GFR, but with an increase in proteinuria when compared with valsartan monotherapy.20 Although in our study only 23 patients had quantifiable proteinuria, we found no differences in proteinuria during follow-up. In the recent study, UK HARP-III, which randomized 414 patients with GF 20−60mL/min/1.73m2 to receive sacubitril/valsartan versus Irbesartan. The main objective of the study was to evaluate the non-inferiority of the first versus the second treatment. The results demonstrated, no inferiority of sacubitril/valsartan versus Irbesartan in the stability of renal function and albuminuria.8 Regarding the potassium values, in our study they remained stable, without changes in the medication such as type of ion exchange resin or the potassium-sparing drugs.

Regarding the dosage, the patients who reached the highest dose were those with a better eGFR, as seen in Table 2. In the TITRATION study, 540 patients were randomized to receive 2 dose escalation regimes to assess tolerability (one conservative and one condensate).21 Although no differences were described in terms of renal function or hyperkalemia in both groups, better treatment adherence was observed in patients who received the most gradual dose escalation.

During the follow-up, an improvement in the LVEF was demonstrated in patients who underwent a control echocardiogram at 6 months, also of the values of Nt-proBNP were reduced with the treatment. Recently, the PIONEER-HF study has demonstrated the ability of sacubitrile/valsartan to decrease Nt-proBNP values in hospitalized patients with HF as compared to enalapril.22,23 It should be remembered that, unlike BNP, the inhibition of neprilysin does not alter the Nt-proBNP values and, therefore this reflects overload of the left ventricle.24

As far as adverse effects and dropouts (10 %), they were similar to those published in clinical trials. The most notable adverse effect in the clinical trials is hypotension and the increase in serum potassium levels.5 However, in our case only one patient abandoned the treatment due to hypotension and there were no adverse events due to increased potassium.

Our work is not exempt from limitations, such as the small sample size, and being perfomed in a single center or the retrospective design itself, a reason why not all data was collected at all times. However, we consider that the results reflect everyday clinical experience with the drug, therefore, they should be taken into account.

In conclusion, the data from our study complement those observed by previous clinical trials but our population was older and with a higher prevalence ofdiabetes. Sacubitrile / valsartan is safe in patients with renal impairment and even offers some degree of renal function improvement. We did not find arterial hypotension or any relevant ionic alterations in patients treated with sacubitrile/valsartan.

BQ and VA have participated in lectures paid by Novartis.