Mapping Progress in Reducing Cardiovascular Risk with Kidney Disease

Introduction

Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality in patients with CKD and patients with ESKD. The pathophysiology of HF in kidney disease is complex, related to “traditional” as well as novel kidney-specific risk factors. There are two subtypes of HF: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). The mechanisms and thus, treatment of HFpEF and HFrEF likely differ. Although the population of patients with kidney disease and concurrent HF continues to grow, knowledge of HF therapies specifically in the CKD and ESKD population remains limited. This article will review known and emerging therapies for HF among patients with CKD and patients with ESKD, briefly summarize the implications of known and novel therapies on current clinical practice, and outline possible areas for further investigation.

Recent Therapeutic Advances in HF in Kidney Disease

Recent studies have investigated new therapies to treat HF and HF complications, targeting known pathways that are activated in HF (e.g., renin-angiotensin-aldosterone system [RAAS] inhibitors) as well as novel pathways that may also have an important role in the pathogenesis of HF in patients with kidney disease (e.g., mineral metabolism). Here, we highlight a few of these new therapies that have been tested in the overall HF population as well as in patients with CKD and patients with ESKD. Evidence specifically for treating HFpEF and HFrEF is discussed when available.

Neurohormonal Modulation

Prescription of therapies, such as RAAS inhibitors, are central in the treatment of HF, particularly HFrEF, and include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and spironolactone. However, a paucity of data on the risk-benefit profile of these medications in CKD limits widespread use. There is fear of complications, such as hyperkalemia and AKI, in CKD. However, newer potassium-lowering agents, such as patiromer, may potentially expand the use and safety of RAAS inhibitors in patients with CKD with HF. Small studies have been promising, but further data are needed.

Furthermore, newer nonsteroidal and highly selective mineralocorticoid receptor antagonists also may minimize hyperkalemia in patients with CKD. In a phase 2 clinical trial of patients with HFrEF and moderate CKD, a nonsteroidal mineralocorticoid receptor antagonist (BAY 94–8862) decreased cardiac biomarkers of hemodynamic stress, with lower rates of hyperkalemia and AKI compared with spironolactone (1). No data are currently available on the use of BAY 94–8862 in patients with ESKD or patients with HFpEF.

Among patients with ESKD treated with dialysis who also have HF, the use of RAAS inhibitors is also suboptimal likely due to poor understanding of possible adverse effects and therapeutic benefits. In addition to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, spironolactone is a potentially important HF therapy in this population. There is promising data in non-United States–based patients with ESKD with HF suggesting that spironolactone may reduce the risk of HF. A trial of spironolactone in the United States hemodialysis population is also ongoing and will provide data on safety and subclinical measures of HF (the SPIN-D; NCT02285920).

Finally, the combination of angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan is among the most promising new agents for the treatment of HF. Sacubitril/valsartan augments RAAS inhibition and the endogenous natriuretic peptide system, and it reduces risk of death and hospitalization among patients with HFrEF compared with valsartan alone (2). A trial of this therapy in patients with HFpEF is going (the PARAGON-HF; NCT01920711). Thus far, there have been no studies of neprilysin inhibitors specifically in patients with CKD or patients with ESKD. This is an important area of further investigation, because many questions remain about ARNIs, including dosing and safety in patients with CKD and patients with ESKD.

Therapies to Improve Mineral Metabolism Dysregulation

Alterations in mineral metabolism are common in patients with kidney disease, and numerous studies have shown a strong link between this axis and risk of HF. However, the trials to specifically test interventions to target mineral metabolism have been disappointing. The PRIMO Study reported that treatment with paricalcitol did not alter left ventricular mass index or diastolic dysfunction in patients with CKD (3). In patients with ESKD, the EVOLVE Trial found that cinacalcet did not significantly reduce the risk of cardiovascular disease in patients with secondary hyperparathyroidism (4). Despite the findings from these initial studies, the mineral metabolism axis remains a promising possible therapeutic target in patients with kidney disease and HF.

Sodium-Glucose Transporter-2 Inhibitors

Sodium-glucose transporter-2 (SGLT-2) inhibitors are clinically available medications that also show tremendous promise as HF therapies. The SGLT-2 inhibitors have several potential cardiac and kidney protective effects, including blockage of sodium/glucose uptake in the proximal tubule, which induces plasma volume contraction and decreases glomerular hyperfiltration. A study of the SGLT-2 inhibitor empaglifozin showed a 38% reduction in the risk of cardiovascular mortality in patients with diabetes and highly significant reductions in HF admissions (5). A trial of another SGLT-2 inhibitor, canaglifozin (the CREDENCE), is ongoing and will include patients with CKD. The primary outcomes will include cardiovascular events and death. However, to date, there are little data on the benefits of SLGT-2 inhibitors in patients with ESKD or by HF subtype, and thus, this remains an important area of investigation.

Soluble Guanylate Cyclase Stimulators

Another class of novel HF therapeutics targets soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide signaling pathway. sGC stimulators produce vasorelaxation and inhibit smooth muscle proliferation, leukocyte recruitment, and platelet aggregation. The SOCRATES-REDUCED Trial and the SOCRATES-PRESERVED Trial tested an sGC stimulator in patients with HFrEF and HFpEF and found no difference in change in NT-proBNP over 12 weeks compared with placebo (6,7). Although these findings were disappointing, the benefit of sGC stimulators as an HF therapy in patients with CKD and patients with ESKD remains unknown and remains an area of interest.

Implications on Current Clinical Practice

Despite the burden and high rates of adverse outcomes in patients with CKD and HF and patients with ESKD and HF, the current clinical management of these patients is largely guided by application of findings from other patient populations, observational studies, or small clinical trials. Until more data are available, the health care team should focus on optimization of clinically available therapies. For example, there are opportunities to improve prescription of β-blockers in patients with CKD and patients with ESKD, particularly for the treatment of HFrEF. In patients with CKD with concomitant HFrEF and patients with ESKD with concomitant HFrEF, observational and small clinical trial evidence suggests that treatment with β-blockers is associated with improved survival. Among patients with kidney disease and HFrEF, use of β-blockers should be encouraged with close monitoring.

Additionally, more individualized approaches to dialysis modality, frequency, and volume management may also benefit patients with ESKD and HF. Peritoneal dialysis may improve New York Heart Association Class and reduce the number of days hospitalized for HF. Hypothesized reasons for these improvements include less dramatic hemodynamic changes, improved control of potassium and sodium, and removal proinflammatory mediators. The effect of hemodialysis frequency on HF risk may also be important to decrease risk of HF. The Frequent Hemodialysis Network multicenter clinical trial compared hemodialysis six times per week with hemodialysis three times per week and found that more frequent dialysis had favorable effects on left ventricular mass index risk of death (8). Thus, greater efforts should be made to expand the use of frequent dialysis and home therapies to the United States ESKD population.

In addition to medical therapies, cardiac devices are commonly used to manage HF and HF complications. With continued improvements in technology, the use of these devices is rapidly expanding. However, recent observational data have suggested that patients with CKD and patients with ESKD may not benefit from left ventricular assist devices or implantable cardioverter defibrillators for the treatment of HFrEF and HFrEF-related complications (9,10). Therefore, although widely available, the risks and benefits of these devices should be carefully weighed in patients with CKD and patients with ESKD until clinical trial data are available on the use of these devices in this patient population.

High-Priority Areas for Therapeutic Advances

There are numerous high-priority areas for research to improve the care of patients with kidney disease and HF. First, the limited data that we do have for the treatment of HF have focused on secondary treatment. However, studies are needed for primary prevention of HF in CKD and ESKD, which may have significant public health effects. Second, many novel HF therapies, such as ARNI and SGLT-2 inhibitors, are clinically available and thus, could be explored further in patients with CKD and patients with ESKD. Third, dedicated studies are needed to examine primary and secondary treatment of HFpEF, which is the more common HF subtype in patients with kidney disease. Prior studies of therapies for HFpEF in the general HF population have been disappointing. Fourth, given the unique pathophysiology of HF in patients with kidney disease, interventions targeted at novel, kidney-specific HF risk factors should be a priority. Fifth, studies focused on implementation of HF therapies in kidney disease are needed to expand the use of clinically available therapies.

In conclusion, further investigation of approaches and therapies for the treatment of HF should be a priority for the research community to improve clinical outcomes for patients living with CKD and patients living with ESKD.

Disclosures

None.