Sacubitril/valsartan in peritoneal dialysis—lessons from a pharmacokinetic study

Patients with chronic kidney disease (CKD) are at increased risk of progression to kidney failure and cardiovascular events [1]. As CKD progresses, the contribution of atherosclerotic disease becomes proportionally smaller, and arteriosclerosis with structural heart disease predominates, potentially explaining the high incidence of sudden cardiac death in patients on dialysis [1]. The similarities in the manifestations of cardiovascular disease observed in advanced CKD and heart failure (HF) populations raises a hypothesis that treatments proven to be effective at treating the HF population may benefit patients with advanced CKD. However, dialysis patients have usually been excluded from trials of HF therapies, including trials of treatments targeting the natriuretic peptide system. Natriuretic peptides have a range of kidney and cardiovascular effects contributing to sodium and water homeostasis and blood pressure (BP) regulation [2]. Neprilysin (NEP) is the key enzyme responsible for degradation of natriuretic peptides [2]. Neprilysin inhibitors (NEPi) raise circulating levels of natriuretic peptides, resulting in a range of beneficial effects including inhibition of the renin–angiotensin system (RAS) and aldosterone production, inducing a potent natriuresis, diuresis and vasodilatation [2]. Therapeutically NEPi must be combined with a RAS inhibitor, as isolated NEPi leads to reflex RAS activation by inhibiting angiotensin II breakdown, counteracting any potentially beneficial effects of increased circulating natriuretic peptides. However, the combination of NEPi and angiotensin-converting enzyme inhibition was shown to be unsafe due to severe angioedema resulting from their joint inhibition of bradykinin degradation [3]. Sacubitril/valsartan (SV) avoids this issue by combining an angiotensin receptor blocker, valsartan, with an NEPi, sacubitril, and was a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI). Following ingestion, SV is separated into its two component drugs. Sacubitril then undergoes further hydrolysis by carboxyl esterases to form sacubitrilat (LBQ657), the active NEPi compound [4]. SV is indicated to reduce the risk of cardiovascular death and hospitalization for HF in adult patients with chronic HF, with benefits most clearly evident in patients with HF with reduced ejection fraction. In the large Prospective Comparison of ARNI to Determine Impact on Global Mortality an Morbidity in Heart Failure Trial (PARADIGM-HF) trial, allocation to SV reduced such risk by 20% compared with enalapril (hazard ratio 0.80; 95% confidence interval 0.73–0.87), with similar effects in those with and without CKD [5]. Rates of elevated creatinine ≥2.5 mg/dL (3.3% vs 4.5%) and potassium >6.0 mmol/L (11.3% vs 14.3%) were both lower in those allocated S/V compared with enalapril [5]. Among patients with HF with preserved ejection fraction, compared with valsartan, SV had no significant effect on rates of total hospitalizations for HF and cardiovascular death in the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial (rate ratio 0.87; 95% confidence interval 0.75–1.01) [6], but improved New York Heart Association (NYHA) class and the Kansas City Cardiomyopathy Questionnaire clinical summary score [6]. There were lower rates of hyperkalaemia among the S/V group compared with the valsartan group (3.1% vs 4.3%) [6]. A recent meta-analysis of 13 trials (including 9674 participants assigned SV and 9693 assigned RAS inhibitors) reported fewer ‘worsening renal function’ events with SV and no difference in risk of hyperkalaemia events [7]. In CKD stages 3 and 4, the United Kingdom Heart and Renal Protection (HARP)-III trial has previously shown that in patients with an estimated glomerular filtration rate (eGFR) of 20–60 mL/min/1.73 m2 treated for 12 months, SV had similar effects on kidney function and albuminuria to irbesartan [7]. SV safely reduced systolic blood pressure by 5.4 mmHg and levels of troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) by 16% and 18%, respectively [8]. There was no significant difference in either the risk of hyperkalaemia (32% versus 24%) or of a 25% eGFR decline from baseline (34% versus 32%) [7]. No large-scale clinical efficacy trial in CKD followed, and there remain several uncertainties about SV use for nephrologists. These include the dosing, efficacy and safety in patients on dialysis. The study by He et al. in this issue sheds some new light on use in peritoneal dialysis [9]. The single-centre open-label, cross-sectional study investigated the effects of SV in adult patients (aged 18–80 years) receiving maintenance peritoneal dialysis, either continuous ambulatory peritoneal dialysis or automatic peritoneal dialysis, for at least a month prior to participation. Participants with hypertension and/or NYHA Class II–IV HF were included [9]. Enrolled participants were designated one of three doses of SV [50 mg (24/26 mg) twice daily, or 100 mg (49/51 mg) once daily (OD) or 100 mg twice daily (BD)] based on their blood pressure, HF ‘condition’ and their clinician's judgement [9]. Patients were required to have discontinued RAS inhibition 36 h prior and were then initiated on SV 50 mg BD with dose titration fortnightly to maximum 100 mg BD, according to blood pressure and hyperkalaemia [9]. Forty patients were recruited, of which 27 (67.5%) patients had hypertension, 4 (10%) had HF and 9 (22.5%) had both conditions. Twenty-six (65%) patients received SV 100 mg BD, 6 (15%) received SV 100 mg OD and 8 (20%) received SV 50 mg BD [9]. Sacubitrilat is predominantly renally excreted [4], and concentrations of sacubitril, sacubitrilat and valsartan in plasma, urine and peritoneal dialysis dialysate were measured by ultra-performance liquid chromatography tandem mass spectrometry. The time SV was taken was recorded and labelled as 0 h, and following SV ingestion, blood samples were collected predose, and 2 h, 4 h and 8 h post-dose, similar to other studies [4, 9]. The maximum plasma drug concentrations (Cmax) in the 100 mg BD group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for sacubitrilat [9]. In multiple-dose pharmacokinetic studies of 200 mg SV daily, steady state Cmax for sacubitrilat in healthy volunteers and people with HF was 10 617 ng/mL and 16 531 ng/mL, respectively [4]. In He et al.’s study, at steady state the exposure to sacubitrilat in the group of patients taking 100 mg BD was similar to that observed in HF populations or patients with CKD not on dialysis [8]. This is perhaps surprising given that 10 participants had anuria and other studies have shown that kidney function is a major determinant of sacubitrilat exposure [8]. UK-HARP-III estimated that each 10 mL/min lower measured GFR was associated with a 1485 (572–2397) ng/mL higher sacubitrilat concentration in people with CKD [8]. Additional sacubitrilat clearance via the dialysate may be one explanation, although the recovery of sacubitrilat from dialysate was modest. Despite high plasma exposure to sacubritrilat, and within the limitations of the design, sample size and presumed short follow-up, He et al.’s study did not identify any safety concerns (including potassium). The non-randomized design precluded reliable quantification of effects on BP and NT-proBNP, with much larger changes (19 mmHg lower systolic BP) observed than one would predict from other data [8, 10]. Nevertheless, this suggests a BP lowering effect (a potential mediator of cardiac benefit) may exist in dialysis patients, contrasting the absence of associations with BP with SV prescription in a small non-randomized study in two dialysis centres in Taiwan [11]. The non-randomized designs of these studies preclude reliable conclusions of any cardiovascular benefits of SV in dialysis patients. Large-scale randomized trials of treatments that can safely address the extraordinary excess risk of cardiovascular disease in patients on dialysis are warranted. The study by He et al. provides useful background information to guide SV dosing in dialysis and to support a larger, randomized study which would inform whether the potential benefits of ARNI in dialysis patients translate into improvements in outcomes that are important to patients, their doctors and healthcare systems. None declared.