*For medical professionals only
“img class=”responsive ” sizes=”(min-width: 320px) 320px, 100vw” src=”https://mmbiz.qpic.cn/mmbiz_png/x5F5KAyDKw19I4VvcibrfNia7lD1fial5KribXqZxjxMxtoc3ichKKz6ib3w5kJias8QNRBYGn80MM0AxEgOvRLib>p>width=”6400″ >Chronic kidney disease (CKD) is one of the most common comorbidities in patients with HFrEF, and among all comorbidities in HFrEF, patients with CKD have the highest population-attributable risk of all-cause mortality and HF hospitalization. In addition, CKD (decrease in estimated glomerular filtration rate [eGFR]) was one of the major determinants of sub-optimal guideline-guided medical therapy (GDMT) use in the CHAMP-HF registry and the BIOSTAT-CHF study The most common reason for not promoting evidence-based therapy in An analysis from TRANSLATE-HF recently showed that the use of guideline-guided medical therapies has declined as CKD progresses. Among patients with an eGFR of 30 to 44 or <30 mL/min/1.73 m2, the use of the 3 categories of evidence-based therapy was 15% and 5%, respectively.
Compared with patients without CKD, HFrEF patients with CKD are at double risk, have a worse prognosis, but receive less evidence-based HFrEF therapy. To complicate matters, many evidence-based treatments may affect renal function both acutely and chronically, making decisions to initiate, titrate, or stop therapy challenging. It is important to note that renal function is dynamic and declining renal function should not always be a cause for concern.
The journal Circulation recently published a review examining the available (or lacking) evidence for GDMT in HFrEF patients with different stages of CKD, providing insights into how to optimize Guidance for monitoring and treating HFrEF patients with CKD. Let’s take a look together.
ARNI
ARNI in HFrEF patients with CKD Efficacy
Although the pivotal PARADIGM-HF trial was published in 2014, ARNI as an alternative to ACEi/ARB or as a The uptake of first-line therapies has been slow. One reason is that HF guidelines have been conservative in recommending ARNIs as first-line therapy (rather than ACEi). With the subsequent ACC/AHA Expert Consensus Decision Approach for Optimizing HF Treatment and the latest updates of other international HF association guidelines, ARNI is recommended as first-line therapy to the same extent as ACEi. Because there is only one large (endpoint-driven) randomized clinical trial in HFrEF, the available evidence in CKD is only from PARADIGM-HF. In subgroup analyses (up to CKD stage 3B), sacubitril-valsartan reduced the primary endpoints of cardiovascular death and hospitalization for HF, as well as all-cause mortality, compared with enalapril. Because patients with CKD stages 4 and 5 were excluded, there is no information on the effectiveness of sacubitril-valsartan (compared with enalapril) in these patients.
Safety of ARNI in HFrEF patients with CKD strong>
In the predefined renal analysis of PARADIGM-HF, the renal composite endpoint of sacubitril-valsartan in CKD patients compared with enalapril was Quantitatively decreased, but not significantly. In the same analysis, compared with enalapril, patients with CKD randomized to receive sacubitril-valsartan had significantly less frequent discontinuation of the study drug for renal reasons. In the PIONEER-HF trial of hospitalized patients with HF, the development of worsening renal function (WRF) between sacubitril-valsartan and enalapril in patients with CKD at baseline was consistent. Efficacy was consistent across all high-risk subgroups, including CKD and no CKD. These findings underscore the renal safety of ARNI use (compared to ACEi therapy) in HFrEF patients with CKD.
The renal effects of ARNI on HFrEF and its interaction with prognosis
Sacubitril-valsartan slowed the decline in eGFR over time compared with enalapril, although the difference was modest. As with other RAAS drugs, ARNIs caused a small decrease in eGFR upon initiation that recovered after discontinuation. The cause of this (pseudo) WRF of ARNI is not fully understood, but may be related to the ARB-related effect of valsartan in combination therapy, or possibly an additional effect of enkephalinase. The latter is also responsible for podocyte alterations, which may account for the small increase in urinary albumin excretion observed with sacubitril-valsartan. When WRF occurs during initiation of ARNI, treatment should be continued (and dose increased) unless the increase in serum creatinine (and potassium) is substantial. Even so, short-term temporary discontinuation is sufficient, and reinitiation of ARNI should be considered if possible.
Practical considerations for ARNI use in HFrEF patients with CKD
The figure below summarizes the impact of ARNI on clinical and renal endpoints in the context of CKD. ARNI was similar to ACEi/ARB in response to changes in serum creatinine and potassium.
SGLT2i
The efficacy of SGLT2i in patients with HFrEF and CKD
SGLT2is is a new class of drugs for the treatment of HFrEF that reduces renal tubular glucose reabsorption and subsequently increases urine glucose and urine sodium (at least initially). This effect was demonstrated in 3 large randomized clinical trials (DAPA-HF, SOLOIST-WHF and EMPEROR-Reduced). The EMPEROR-Reduced study focused on recently hospitalized patients with heart failure, including patients with preserved ejection fraction, treated with SGLT1/2 inhibitors. In EMPEROR-Reduced, the lower limit of eGFR in the included trials was 20 mL/min/1.73 m2, while the lower limit of eGFR in other studies was 30 mL/min/1.73 m2. In all trials, SGLT2i had a clear benefit in CKD stages 1 to 3B. For CKD stage 4, only EMPEROR-Reduced published data on the combined endpoint of cardiovascular death and HF hospitalization with this treatment. The study confirmed that empagliflozin significantly reduced the risk of this endpoint compared to placebo. There are no data on SGLT2i in patients with HFrEF and CKD stage 5.
Safety of SGLT2i in patients with HFrEF and CKD
SGLT2i reduced the risk of renal function endpoints in patients with HFrEF regardless of CKD. In patients with DAPA-HF, there was a significant reduction in serious renal events in the SGLT2i-treated group compared with placebo, a result also confirmed in the EMPEROR-HF study.
The renal effect of SGLT2i on HFrEF and its interaction with prognosis
The early eGFR after initiation of SGLT2i was significantly decreased, with an average of 4 mL/min/1.73 m2. However, eGFR declined more slowly in the SGLT2i group compared with placebo over a longer period of time. Significant increases in serum creatinine were extremely rare in the SGLT2i group.
Small-sample studies show that measured (not estimated) GFR decreases after SGLT2i is activated. However, no studies have been published on its effects on renal hemodynamics (eg, renal blood flow [RBF]). It can be speculated that, at least in acute conditions, SGLT2i can cause more sodium ions and chloride ions to stimulate the dense plaque at the distal end, and cause vasoconstriction of afferent arterioles through activated bulbar feedback. However, in a mechanistic study in patients with type 2 diabetes (non-HF), SGLT2i induced changes in GFR, possibly due to efferent vasodilation rather than afferent vasoconstriction. However, this change is reversible. In most cases, this decline is likely pseudo-WRF, so the beneficial effect of SGLT2is on clinical outcomes and long-term preservation of renal function cannot be ignored and should be continued.
Currently, patients with stage 4 and 5 CKD are excluded from the current SGLT2i study. Even though the inclusion and exclusion criteria in the SCORE trial were relatively loose, at baseline, only 9% of participants had stage 4 CKD. Additional data were mainly from the DAPA-CKD study and the CREDENCE study. In both studies, with or without diabetes, 10% to 15% of patients receiving canagliflozin or dapagliflozin experienced significant reductions in renal function events and cardiovascular events. The results of this study confirmed the safety and efficacy of SGLT2i in patients with eGFR. But in both studies, patients with eGFR <25 (DAPA-CKD) or 30ml/min/1.73 m2 (CREDENCE) were also excluded.
Practical application of SGLT2i in patients with HFrEF and CKD strong>
SGLT2i inhibitors are the only class of HFrEF drugs that have been systematically studied in more severe CKD categories and have been shown to slow eGFR over time decline. Therefore, in patients with grade 4 CKD (with appropriate laboratory monitoring), these drugs are safe to use. In addition, SGLT2is can be used in fixed doses and does not require titration. Moreover, SGLT2i does not increase serum potassium, so hyperkalemia has less effect on SGLT2.
Vericyg
Efficacy and safety of velociguat in patients with HFrEF and CKD
Currently The only phase 3 trial to evaluate the clinical benefit of veliciguat in the HFrEF population is the VICTORIA trial. The lower limit of eGFR set in the study was 15 mL/min/1.73 m2, and 15% of participants were ultimately between 15 and 30 mL/min/1.73 m2, and patients with CKD stage 5 were excluded. There are no subgroup studies to investigate the effect of veliciguat on all-cause mortality in different eGFR subgroups.
In the VICTORIA study, veliciguat did not reduce the incidence of cardiovascular death in the entire trial population and in patients with CKD stages 3 and 4. For the combined endpoint of cardiovascular death and HF hospitalization (the primary endpoint of VICTORIA), there was no favorable evidence of an interaction of veliciguat treatment with eGFR, nor evidence of impairment.
Veliciguat did not show excessive adverse events compared with placebo in patients with stage 4 CKD enrolled in the study. In all CKD stages, the event of drug discontinuation due to WRF after initiation of treatment did not differ significantly between the drug and control groups.
The renal effects of veliciguat on HFrEF and its interaction with prognosis< /span>
From a physiological point of view, veliciguat can reduce oxidative stress, increase circulating GMP, and improve clinical HF prognosis. Improve or preserve GFR in HF patients. However, in the VICTORIA study, the reduction in eGFR was greater than placebo in the first 16 weeks after initiation of veliciguat treatment, but this difference was not significant after 48 weeks of treatment.
Velixiguat in HFrEF patients with CKDPractical application
In international guidelines, veliciguat can be used in patients with HFrEF and severe CKD stage 4, because the patients included in VICTORIA have an eGFR ≥ 15 mL/min/1.73 m2. However, as with any evidence-based HF treatment, regular monitoring of vital signs, serum creatinine, and serum potassium levels is required with veliciguat.
Omecamtiv mecarbil
Omecamtiv mecarbil for patients with HFrEF and CKD The efficacy and safety of
The GALACTIC-HF trial is the only large RCT to evaluate the efficacy of Omecamtiv mecarbil on clinical endpoints of HFrEF. The study excluded patients with eGFR <20 mL/min/1.73 m2 at baseline. On the all-cause mortality endpoint, 0mecamtiv mecarbil treatment did not reduce the risk of death, and there was no benefit in the CKD stage subgroup. Following Omecamtiv mecarbil treatment, the primary outcomes of cardiovascular death and hospitalization for heart failure were slightly reduced compared to placebo, with no significant interaction of eGFR and treatment effect on the primary outcomes. This benefit profile was less effective in patients with CKD stage 3A/3B. There are currently no data investigating the renal safety of Omecamtiv mecarbil.
Renal effects of Omecamtiv mecarbil on HFrEF and its interaction with prognosis
There are limited data on the effect of Omecamtiv mecarbil on renal function in patients with HFrEF. In GALACTIC-HF, changes in serum creatinine were similar between Omecamtiv mecarbil and placebo after 24 and 48 weeks of treatment. In the ATOMIC-AHF study, the renal safety profile of intravenous Omecamtiv mercabil was similar to placebo, as was the rate of WRF progression.
Practical application of Omecamtiv mecarbil in patients with HFrEF and CKD< /strong>
Omecamtiv mecarbil is approved for the treatment of HFrEF and can be used in patients with HFrEF and severe CKD stage 4. Dosing requires continuous monitoring of drug levels to achieve therapeutic target drug concentrations, as well as monitoring of vital signs and serum electrolytes. Additionally, Omecamtiv mecarbil has no effect on serum creatinine (or potassium), nor should WRF and hyperkalemia be considered.
Scientific interpretation of randomized clinical trial results in HFrEF patients with CKD
Implementing guideline-guided treatment and translating clinical trial results into clinical practice are two of the most challenging aspects of improving the management of patients with HFrEF. Physicians are hesitant to initiate or continue treatment in patients with HFrEF for many reasons, but one of the most important is progressive renal impairment, concomitant hyperkalemia, and symptomatic hypotension. Many high-risk patients, including those with severe CKD, would be ineligible for treatment if RCT criteria were strictly followed. In addition, the safety of these drugs is closely monitored in RCTs. These trials also used strict dose reduction or discontinuation when certain renal function changes or hyperkalemia occurred. Therefore, extrapolating the results of large clinical trials into clinical practice is challenging.
Rigorous laboratory evaluation and follow-up is important when initiating or altering GDMT, especially if it may affect GFR or serum potassium. Assessment of serum creatinine and electrolytes should be performed at different stages: at initiation of medication, at each dose change, at maximum dose, and at further exacerbations. Standard follow-up in patients with CKD should be considered every 4 to 6 months, depending on the stability of the clinical condition.
As HF clinicians increasingly face aging, frail, and sickly HFrEF populations with more comorbidities and more severe CKD, trials must The aim is to reduce restrictions on patient inclusion criteria so that trial results can be more easily generalized to clinical practice. The impetus for this change may need to be driven by regulators rather than drug companies.
Although data are limited, there is consistent evidence that, with adequate monitoring, most evidence-based medical therapy for HFrEF achieves at least stage 3 CKD (eGFR 30 mL/ min/1.73 m2) efficacy and safety. In addition, in newer classes of drugs for CKD (SGLT2i, ARNI), there is particularly strong evidence that there may even be renoprotection. The efficacy and safety of these pharmacotherapies varied (Figure 3).
It is worth noting that there are several therapies that temporarily reduce eGFR after initiation but remain effective in preventing HF events and are associated with long-term stabilization of renal function. In all cases, it should not be the height or change in serum creatinine that determines the change in the prescription of evidence-based therapy, but the change in the patient’s clinical status.
Summary
CKD plays a crucial role in the pathophysiology and prognosis of HFrEF, and is often considered a limitation in optimizing evidence-based therapy for HFrEF. However, available evidence suggests that most guideline-directed medical therapies are effective until CKD stage 3B, and some drug classes even show efficacy in CKD stage 4. Many treatments directly or indirectly affect kidney function, and related conditions, such as hyperkalemia, require close monitoring when treatment is initiated. The expected decline in eGFR upon initiation of RAASi (including ARNI) and SGLT2i should not be a reason to discontinue these life-saving drugs.
Source:
Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease. Circulation. 2022 Mar;145(9):693-712. doi: 10.1161/CIRCULATIONAHA.121.052792.
Author:Zhao Zixu Capital Medical UniversityAffiliated Beijing Anzhen Hospital
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