Optimising heart failure treatment for patients on peritoneal dialysis

All patients with end-stage kidney disease on renal replacement therapy have increased risk of cardiovascular disease. This has been written a lot over the years and, undeniably, it is true. The processes that drive cardiovascular disease in this population are different to the general population, and the unique conditions of renal failure lead to pathological changes in cardiovascular structure and function. These changes include left ventricular hypertrophy, left ventricular cavity dilatation, stiffening of the major arteries and increasing levels of diffuse interstitial myocardial fibrosis. These pathological processes all associate with adverse cardiovascular outcomes and often lead to the development of overt systolic heart failure.

The development of heart failure is common for patients on peritoneal dialysis (PD; Wang et al., 2011) and, for patients with established heart failure, PD is often viewed as a “gentler” alternative for those fit for and requiring renal replacement therapy. Despite this, optimising heart failure medications for patients on any dialysis therapy has long been a problem for a variety of reasons, particularly hyperkalaemia associated with ACEi/ARB/MRA therapy, hypotension (all antihypertensives) and lack of effect of diuretics. PD patients are also fewer and fewer in number, making definitive studies of efficacy and effectiveness challenging. Consequently, the publication of a small study in Nephrology Dialysis Transplantation by He and colleagues is most welcome, with their assessment of the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients on PD. SV combines the neprilysin inhibitor sacubitril with the ARB valsartan, and is a prognostically important medication for the treatment of heart failure with reduced ejection fraction for many patients, improving outcomes compared to ACE-inhibition (McMurray et al., 2014), but is sparsely used in patients with kidney failure.

So, what did the study do? It enrolled 40 patients on PD who had either heart failure (NYHA 2–4) or hypertension, and assessed the effect of SV at either 50 mg twice daily, 100 mg once daily or 100 mg twice daily (dependent on and titrated to patient baseline blood pressure and degree of heart failure with clinical judgement). They monitored patients for adverse side-effects and changes in blood pressure after starting and titrating the medication, but, importantly, they also assessed concentrations of the drug(s) in the urine, blood and peritoneal dialysis fluid with mass spectrometry. Twenty-six of the 40 patients were titrated to a dose of 100 mg BD, and the drug appeared well tolerated with no major adverse reactions and no changes in biochemical tests. As would be expected, there was a significant drop in systolic and diastolic blood pressure, with an improvement in ejection fraction of around 10% (measured by echocardiography). An improvement in ejection fraction of 10% would seem a rather optimistic take-home from such a small study, but encouraging nonetheless.

The amount of drug excreted in the urine was lower than is documented in patients without renal failure and, as would be anticipated, was higher in patients with greater preservation of residual renal function. The drugs were not well cleared by peritoneal dialysis. So, in this study, neither residual renal function nor PD contributed a great deal to the elimination of SV, but maximal concentrations of sacubitril did not exceed values described in healthy volunteers. The authors conclude that the drug is likely to be safe for patients with renal failure and starting at 50 mg twice daily with titration seems sensible (and likely necessary).

So, why am I highlighting this small mechanistic study? Well, simply because it offers hope and encouragement against the prevailing therapeutic nihilism that can face these patients. Do the results mean SV can be dished out without due care and attention? No. Is it safe to try in patients where clinically indicated? Probably – in discussion with heart failure specialists and with appropriate monitoring. Is this an area that is ripe for further study in a wider variety of chronic kidney disease and end-stage kidney disease populations? Absolutely.

A digest of the study can be read here.

References

McMurray JJ, Packer M, Desai AS et al.; PARADIGM-HF Investigators and Committees (2014) Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371: 993–1004.

Wang AY, Wang M, Lam CW et al. (2011) Heart failure in long-term peritoneal dialysis patients: a 4-year prospective analysis. Clin J Am Soc Nephrol 6: 805–12.