Cardiorenal Crosstalk in Patients with Heart Failure

Round 1

Reviewer 1 Report

1. ACEIs/ARBs: the authors should discuss the monitoring of serum creatinine and serum potassium after the initiation of these therapies in patients with HF and CKD. How should clinicians interpret the expected serum creatinine rise?
2. SGLT-2 inhibitor and MRA trials in HF should be summarized in 2 separate trials. The design and main results of these trials should be clear to the readers.
3. The recommendations for dose adjustments presented in Table 1 are not clear to the reviewer. Are these recommendations based on pharmacokinetic studies conducted in advanced CKD?
4. The authors should discuss that the pharmacokinetic properties of several drugs are substantially altered in the patients with moderate-to-severe kidney dysfunction. For example, spironolactone is a drug with active metabolites that have renal excretions and accumulate over time in patients with eGFR of 25-45. This issue was illustrated in the AMBER trial.
5. Please discuss the recent Cochrane meta-analysis regarding the safety and efficacy of steroidal MRAs in CKD (Cochrane Database Syst Rev. 2020;10:CD007004).
6. Please discuss the more recent clinical-trial data with the non-steroidal MRA finerenone (the FIDELIO-DKD and FIFARO-DKD trials) and some phase II trials that explored the efficacy of finerenone in patients with HFrEF.
7. The review should also include a small section to discuss the potential benefit of peritoneal dialysis in patients with severe HF and CKD. In such patients, particularly when resistance to diuretic therapy is developed, the initiation of peritoneal dialysis may be a salvage therapy to improve the volume status, to reduce the incidence of recurrent hospitalization and possibly to improve health-related quality of life.  

Author Response

Dear Reviewer,

We are thankful for the careful and thoughtful analysis of our manuscript . We have addressed your suggestions point by point below:

Comment #1 ACEIs/ARBs: the authors should discuss the monitoring of serum creatinine and serum potassium after the initiation of these therapies in patients with HF and CKD. How should clinicians interpret the expected serum creatinine rise?

 

Reply. We thank the reviewer for pointing out this important issue. We discussed it in the section “Consideration on RAAS antagonists”.

 

“In daily practice, treatment with RAAS blockers should not be discontinued with small-scale decrease of GFR in HF patients. According to 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, an increase in creatinine of > 50% above baseline, or 266  µmol/L creatinine, or an eGFR <25 mL/min/1.73 m2, whichever is the smaller, is acceptable.(47) In this case, the patient should be evaluated thoroughly and the assessment should exclude renal artery stenosis, excessive hyper- or hypovolaemia, concomitant medication and hyperkalaemia. If the creatinine level remains elevated despite adjustment of concomitant medications, the dose of RAAS inhibitors should be halved and blood chemistry re-checked within 1-2 weeks. Serum creatinine, BUN, and serum potassium should be rechecked frequently (at least weekly) until levels have stabilized.”

 

 

Comment #2 SGLT-2 inhibitor and MRA trials in HF should be summarized in 2 separate trials. The design and main results of these trials should be clear to the readers.

 

Reply. SGLT-2 inhibitor and MRA trials design have been detailed in the corresponding sections.

 

Comment #3 The recommendations for dose adjustments presented in Table 1 are not clear to the reviewer. Are these recommendations based on pharmacokinetic studies conducted in advanced CKD?

 

Reply. We thank the reviewer for this clarification. These recommendations are based on available clinical evidence and the SWISS medicinal product licensing body (SWISSMEDIC).

 

Comment #4 The authors should discuss that the pharmacokinetic properties of several drugs are substantially altered in the patients with moderate-to-severe kidney dysfunction. For example, spironolactone is a drug with active metabolites that have renal excretions and accumulate over time in patients with eGFR of 25-45. This issue was illustrated in the AMBER trial.

 

Reply. We discussed the pharmacokinetic properties of spironolactone in the « MRA in diabetic kidney dysfunction » section.

 

“This increased risk may relate to the substantial change of pharmacokinetic properties of spironolactone in patients with moderate-to-severe kidney dysfunction as suggested from the AMBER randomized trial, in which spironolactone (25 to 50 mg/d) was administered for 12 weeks as add-on therapy in patients with resistant hypertension and moderate CKD (eGFR of 25 - 45 ml/min per 1.73 m2).(40) After stop of treatment, more than half of the initial blood pressure reduction remained sustained for another 2 weeks after drug discontinuation, which suggests accumulation of active metabolites of spironolactone in the circulation of these patients. This can also explain why discontinuation of spironolactone treatment for hyperkalemia may not restore normokalemia immediately.”

 

Comment #5 Please discuss the recent Cochrane meta-analysis regarding the safety and efficacy of steroidal MRAs in CKD (Cochrane Database Syst Rev. 2020;10:CD007004).

 

Reply. As requested, we discussed the recent Cochrane meta-analysis in the « MRA in HFrEF with kidney dysfunction” section.

 

“A recent Cochrane meta-analysis including 44 studies suggests that aldosterone blockade may reduce proteinuria and kidney function when added to ACEi or ARB.(38) However, treatment effects did not prevent progression of CKD towards kidney failure, and did not reduction of major cardiovascular events or all-cause death. Furthermore, this Cochrane analysis suggestsed that aldosterone antagonists in combination with ACEi or ARB (or both) increase the risk of hyperkalaemia, similar to result from the RALES."

 

Comment #6 Please discuss the more recent clinical-trial data with the non-steroidal MRA finerenone (the FIDELIO-DKD and FIFARO-DKD trials) and some phase II trials that explored the efficacy of finerenone in patients with HFrEF.

 

Reply. We thank the reviewer for this point. We discussed more recent clinical-trial data with the non-steroidal MRA in the « MRA in HFrEF with kidney dysfunction” section.

 

“Recent clinical trials have demonstrated efficacy of the novel, selective, nonsteroidal MRA finerenone to slow progression of kidney and cardiovascular disease, including HF, in patients with CKD and type 2 diabetes. Barkis et al. demonstrated in a phase II trial that the addition of finerenone resulted in an improvement in the urine albumin-to-creatinine ratio in patients with diabetic nephropathy when compared with placebo.⁽¹⁾ The FIDELIO-DKD trial demonstrated furthermore a favourable effect on cardiorenal outcomes in T2DM patients with predominantly CDK stage 3 and 4.⁽²⁾ Finally, the FIGARO-DKD trial, which randomized 7437 patients to finerenone or placebo, showed beneficial effects of finerenone on CV outcomes among patients with T2DM and CKD. This beneficial effect was mainly driven by a reduction in the incidence of hospitalization for HF.⁽³⁾ “

 

 

 

Comment #7 The review should also include a small section to discuss the potential benefit of peritoneal dialysis in patients with severe HF and CKD. In such patients, particularly when resistance to diuretic therapy is developed, the initiation of peritoneal dialysis may be a salvage therapy to improve the volume status, to reduce the incidence of recurrent hospitalization and possibly to improve health-related quality of life

 

Reply. We added a section on ultrafiltration.

 

“Despite optimal treatment of heart failure, some patients will progress towards advanced stage of renal failure.  Resistance to diuretics, renal dysfunction and refractory congestion frequently complicates advanced heart failure. Ultrafiltration through hemodialysis or peritoneal dialysis can be alternative options to treat fluid overload. The UNLOAD trial demonstrated that ultrafiltration safely produces greater weight and fluid loss when compared with intravenous diuretics.(60) In these patients, especially when resistance to diuretic therapy develops, the initiation of ultrafiltration may be a salvage therapy to improve volume status and reduce the incidence of recurrent hospitalizations.”

Reviewer 2 Report

This review addresses a not new but clinically relevant topic. Here are my reflections:

- the division of paragraphs by class of drugs and clinical phenotypes is useful

- updated to the new classes of drugs recommended in the most recent guidelines

- the problem on the definition of WRF (worsening renal function) is not adequately addressed and it would be advisable to clarify the clinical "setting" of decompensation (acute vs. chronic)

- the review examines clinical trials on heart failure that have significant limits in patient selection (for example under-representation of patients with advanced CKD, women, obese, etc.) it would be appropriate to add a paragraph on what real life studies say as in this setting, renal dysfunction may represent one of the reasons why the therapy recommended by the guidelines is not performed

- the role of right ventricular decompensation in the increase in systemic and abdominal venous pressure is very approximate. It should be examined in depth considering the emerging possibility of correcting tricuspid insufficiency by "clip"

 

in conclusion I appreciate the efforts of the authors and the review is potentially useful but in the present form it is definitely incomplete

Author Response

Dear Reviewer,

We are thankful for the careful and thoughtful analysis of our manuscript . We have addressed your suggestions point by point below:

This review addresses a not new but clinically relevant topic. Here are my reflections:

- the division of paragraphs by class of drugs and clinical phenotypes is useful

- updated to the new classes of drugs recommended in the most recent guidelines

Comment #1 the problem on the definition of WRF (worsening renal function) is not adequately addressed and it would be advisable to clarify the clinical "setting" of decompensation (acute vs. chronic)

Reply. We acknowledge the limitations due to the definition of WRF in the different studies and discussed it in the introduction section.

“Many HF studies have defined worsening renal function (WRF) as a decrease in eGFR, but there is great variability in WRF definition and the biomarkers used for grading severity of WRF vary (serum creatinine, cystatin C, or estimated GFR). This inhomogeneity makes it difficult to compare studies with each other. For example, when WRF is defined by the increase in absolute creatinine, it inhomogeneously weights the percentage of worsening of renal function between patients with mild and moderate to severe CKD. Nonetheless, there is a general consensus that WRF is an increase of 26.5 µmol/L of serum creatinine, as this increase is associated with a significant elevation in the risk of mortality and morbidity.(17,18)”

Comment #2 the review examines clinical trials on heart failure that have significant limits in patient selection (for example under-representation of patients with advanced CKD, women, obese, etc.) it would be appropriate to add a paragraph on what real life studies say as in this setting, renal dysfunction may represent one of the reasons why the therapy recommended by the guidelines is not performed

Reply. We added a section on real world studies

“Due to strict eligibility criteria for HF patients included in randomized controlled trials (RCT), study results are often considered to be of limited applicability for real-world HF patients while registry data are thought to map the typical HF patient more accurately. However, recent results obtained from a retrospective observational study including 17,106 de novo HFrEF patients indicate that higher treatment intensity is associated with lower mortality and lower rehospitalization risk.(16) Moreover, triple GDMT HF therapy at discharge was associated with a 32% decrease of the incidence of death or rehospitalization. These results extend the applicability of the RCT findings to HF patients with a more severe comorbidity burden, as 54% of the study participants had diabetes and 34% had CKD.”

Comment #3 the role of right ventricular decompensation in the increase in systemic and abdominal venous pressure is very approximate. It should be examined in depth considering the emerging possibility of correcting tricuspid insufficiency by "clip"

Reply. We thank the reviewer for raising this interesting point and added a section on transcatheter Interventions for tricuspid valve disease.

« Tricuspid regurgitation (TR) is common in patients with left-sided valvular heart disease and  is an important prognostic marker among HFrEF patients. Recently, minimal invasive catheter-based techniques have emerged as a feasible and effective option for TR treatment in selected high-risk patients who would clinically benefit from tricuspid valve repair.

The TRILUMINATE feasibility study, showed promising results of the TriClip system in terms of TR reduction, low mortality, improvement in quality of life, and right atrial and ventricular modeling.⁽⁶⁶⁾ The effect of this treatment on renal outcomes remains unclear- However, elevation of central venous pressure is an important risk factor for kidney dysfunction in acute heart failure as suggested from data of the ADHERE registry and the ESCAPE trial.^(67,68) A curvilinear inverse relationship between eGFR and central venous pressure was shown in 2557 stable patients with cardiovascular disease. Moreover, this study also indicated an independent association between central venous pressure and all-cause mortality.⁽⁶⁹⁾ Altogether, reduction of right atrial pressure with subsequent decrease of the central venous pressure should provide beneficial effect on renal outcomes.”

Round 2

Reviewer 1 Report

I have no additional comments to the authors.

Reviewer 2 Report

Well done.

"Per Aspera ad Astra"