Successful Treatment of Severe Heart Failure in Advanced Diabetic Kidney Disease Using Angiotensin–neprilysin Inhibitors (Sacubitril/Valsartan) – Report of Two Cases with Review of Options in Literature

Introduction

The heart and kidney interact in a complex and bidirectional manner. Heart failure (HF) is one of the leading causes of emergency department visits and hospitalizations in patients with advanced stages of chronic kidney disease (CKD), more so in dialysis patients.[1] There is paucity of data on the efficacy and safety of established treatments of HF among advanced CKD population because such patients are excluded in the majority of clinical trials. Clinicians often get dissuaded from initiating standard therapy resulting in poorer outcomes. Synergistic collaboration of nephrologists and cardiologists may aid in implementing guidelines-directed strategy to improve patient outcomes. We report our experience of two such cases with follow-up observation, where the appropriate use of angiotensin receptor – neprilysin inhibitor (ARNI) (sacubitril/valsartan) in advanced CKD resulted in good quality of life and avoidance of recurrent hospitalization.

Discussion

Patients with CKD are at increased risk of cardiovascular disease and often present with HF (two to three times higher risk, incidence around 15% in late stage).[12] The risk of HF increases with worsening proteinuria and declining GFR independently.[3] Conversely, patients with HF frequently have reduced kidney function (approx. 40%).[4] Regardless of whether HF begets CKD or vice versa or both developing and progressing simultaneously, prognosis of patient with HF and CKD stage 4–5 is poor[5]. It is estimated that the survival rates in CKD stages 4–5 with HF are below 40% at second year[45] and are far worse in a small subset of CKD population with heart failure with reduced ejection fraction (HFrEF).

HF in CKD is often underdiagnosed and could be confused with fluid overload, anemic symptoms, or uremic manifestation as there is lot of overlap in symptoms. To compound the problem, around 50–75% of CKD patients have structural heart disease as LVH on 2D echo, which may or may not be related to symptoms of dyspnea. Biomarkers like N terminal brain natriuretic peptide (NT-BNP) and Troponin I are more prognostic than diagnostic though serum ST2 could be a tool to assess HF better in CKD.[1]

Treatment for HF in CKD is based on two broad principles: (i) to target pathophysiological links between CKD and HF to prevent HF and (ii) to improve overall prognosis in established HF.[6] The main objectives of HF therapy in CKD (as well as in non-CKD) patients are to decrease the preload and after load and to reduce LVH, treat myocardial ischemia, and inhibit neurohumoral hyperactivity, especially the sympathetic nervous system and RAS (renin angiotensin system). The anatomical substrates of HF (LVH, vascular calcification, etc.) develop early in CKD and strategies to prevent it have not been rigorously tested in the CKD populations. RAS inhibition is the cornerstone of HFrEF treatment. The fear of deterioration of renal function and hyperkalemia results in reluctance to contemplate its use in advanced CKD among physicians, cardiologists, and even nephrologists and is often associated with treatment discontinuation of RAS inhibition. This decision to discontinue RAS blockade is especially disadvantageous in HFrEF patients with CKD, who are at particularly high risk of adverse cardiac and renal outcomes. These patients also have the greatest absolute risk reduction with RAS inhibition. [78] A trend of stable serum creatinine is a far better predictor of a good outcome than a single value even if there is initial rise of serum creatinine not exceeding 20% from baseline.

Neprilysin inhibition with ARNI is the most recent treatment that plays a key role in not only improving outcomes in HF but also favorably impacting CKD progression[910] Switching therapy in an eligible HFrEF patient from a RAS-blocker to ARNI has been reported to induce beneficial reverse remodeling of metrics of systolic and diastolic function (rise of EF 10%) and renal function stabilization (reversal of type 2 CRS), which makes it the most preferred drug in this setting. Even overtly proteinuric CKD patients on neprilysin inhibition had reduced cardiac biomarkers levels more than in patients on irbesartan.[11] Experiments using 5/6 nephrectomy models suggested that NEPI reduces proteinuria and histological markers of kidney damage more than ACE inhibition alone.[12] ARNI has additional BP lowering properties, which is a common problem in CKD population and may play a role in reducing the progression of CKD. Hence, ARNI is not only cardioprotective but also renoprotective.

The pathophysiologic mechanisms responsible for benefits of ARNI remain unclear. The benefit analysis of ARNI is done at three spheres: effect on biomarkers, cardiac reverse remodeling, and effect on functional capacity. Neprilysin inhibition enhances circulating levels of biologically active natriuretic peptides and other vasoactive peptides that may have favorable vasodilatory, antifibrotic, and antihypertrophic effects. Favorable effects of neprilysin inhibition are also due to improvement in myocardial remodeling (assessed by focused echocardiographic end points like left ventricular end-diastolic and end-systolic volumes, left atrial volume, mitral E/e′ ratio) and wall stress though one may fail to demonstrate significant difference in contractile properties as assessed (left ventricular ejection fraction and global longitudinal strain) or ventricular–vascular coupling (Ea/Ees ratio) as was the case in our patients.[13]

It is well known fact that one-third of HF patients die within 1 year after diagnosis with greatest risk of mortality in first three months.[14] Similarly, nearly 30% patients of HF patients need hospital readmission in 1 year. Such high mortality and readmission rates are favorably influenced by goal directed therapy with use of ARNI.[8] ARNI minimizes functional deterioration and positively impacts NYHA functional class.

As majority of patients in late stages of CKD are resistant to diuretics for volume control, fluid removal is better achieved with either HD or PD.[15] Patients in this advanced stage of CKD benefit more with frequent dialysis (slow long nocturnal HD) or PD for mitigating HF. Several studies have shown that PD in HF significantly improves NYHA Class and reduces the number of days hospitalized for HF.[16] Myocardial stunning during HD as assessed by cardiac PET scans is linked to further decline in LVEF of almost 10% a year increasing risk of CV death further. Ultrafiltration by PD in this context is found to be safer. Patients with HF tend to do better with PD compared to HD in long term. Such approach can be utilized to supplement slow ultrafiltration, prevention of hyperkalemia, improving or stabilizing LV function, and preserving residual renal function.

Usage of ARNI is promoted as a grade 1a recommendation in recent guidelines for treating HFrEF among patients with eGFR >30 ml/min.[8917] It is suggested in advanced kidney disease to initiate with low dose (50 mg twice) and titrate up to 100 mg twice daily in the maintenance phase, though one may use even 200 mg twice daily if tolerated.[18] We noted similar results in both our patients who were at highest risk for death and hospitalization due to diabetic status, triple vessel disease, reduced EF, and advanced CKD. ARNI positively impacted the quality of life in both of our patients (first returned to his outdoor business activity and the second was independent for his daily self-care.

Conclusion

HF with CKD is riddled with diagnostic dilemmas and poses multidimensional challenges like hyperkalemia, deterioration of renal function, and diuretic resistance. Multipronged strategy including PD, newer agents for potassium control like patiromer or sodium zirconium silicate may allow the use of agents like RAS inhibitors, ARNI, MRA (mineralocorticoid receptor antagonist) in these patients. ARNI looks promising as a treatment option that could reduce the risk of HF safely even among patients with CKD stage V. Our limitation is to draw inference from only these two well-followed patients. However, the utility of such therapy has to be scrutinized carefully by real world experience involving a sizeable number of patients in a multicentric-pooled data having long-term follow-up for reliable assessment of such therapeutic intervention. Our report suggests that one should not deprive these high-risk patients the benefits of ARNI by contemplating its use even in late stages of advanced CKD with close monitoring.