This study evaluated data from a contemporary multicenter registry of acute HF cases and revealed three main findings. First, among patients with HFrEF, malnutrition (based on a low GNRI score) was associated with significantly lower rates of GDMT use. Second, patients with malnutrition had an increased risk of the composite outcome that involved all-cause death and HF rehospitalization. Third, even among patients with malnutrition, increased use of GDMT was independently associated with lower risks of the composite outcome of rehospitalization or all-cause mortality.
Treatment for HF aims to prevent morbidities and prolong morbidity-free survival. Combination therapy using RASis (i.e., ACEis/ARBs/ARNIs and MRAs) with BBs is a guideline-recommended standard therapy for patients with HFrEF. However, despite increased awareness of this recommendation, a study of the CHAMP-HF registry demonstrated that prescription rates for these disease-modifying drugs remain lower than expected in the ambulatory setting and have not improved over 15 years since the Euro Heart Survey on Heart Failure [9, 28]. Similarly, a study on acute HF patients hospitalized with HFrEF from the Japanese Cardiac Registry of Heart Failure (2004–2005) revealed low proportions of drug use at discharge (BBs: 57.9%, ACEis: 4.3%, ARBs: 45.6%, MRAs: 46.0%) [29]. Aside from the rate of BB use, our findings are generally comparable and suggest that there is room for improvement in the treatment rates of ACEi/ARB and MRA, similar to that observed in Western countries. Additionally, the rate of MRA administration was similar across nutritional status. The purpose of its use may have been different than that of the other two agents and it may be prescribed as a potassium-sparing diuretic more frequently than as a cardioprotective agent. This may have influenced the relationship between its administration and GNRI value.
The gaps in GDMT use in this setting may be related to various factors, including physician aversion and inertia, patient intolerance, and side effects [9]. Frailty, a possible reason for physicians being hesitant to change therapy, is also strongly related to malnutrition, but has different features that require investigation and call for further evaluation of the interaction and its association with HF treatment and outcomes, since either of the two may lead to a vicious cycle of physical impairment. In previous studies, patients with low GNRI were more likely to have characteristics of frailty, which represents a state of increased vulnerability to stressors resulting from multisystem dysregulation and is associated with a higher risk of impaired physical function and mortality [30]. As our study showed that GDMT use was associated with better outcomes even in patients with low GNRI, it may be possible to improve their prognoses.
Malnutrition may make physicians reluctant to alter a patient’s treatment considering the medicine’s side-effects during liver dysfunction [16], as it decreases oxidative metabolism in the liver, which is performed by cytochrome P-450 isoenzymes, via depletion of nicotinamide adenine dinucleotide phosphate reserves. Other liver metabolic pathways can also be impaired, which can decrease drug clearance, thereby increasing drug exposure and potentially resulting in harmful side effects. There are also concerns regarding drug absorption changes due to poor nutritional status (e.g., because of vitamin and/or mineral deficiency), which may influence the physician’s decisions based on the medication’s effectiveness and potential side effects [31] and partially explain the present study’s findings. Moreover, the existing RCTs have generally excluded malnourished patients, who are often older and have more comorbidities. Thus, although there is still limited evidence regarding whether nutritional status influences the effectiveness and side effects of GDMT, our results suggest that even malnourished patients with HFrEF can benefit from a more complete prescription of GDMT.
Malnourished patients are often older and tend to have a greater number of comorbidities, including renal dysfunction, which may make physicians hesitant to add new medications [32]. We have previously reported that RASi prescriptions were more appropriate for patients with better renal function (eGFR: >30 mL/min/1.73 m2), and RASi prescription was associated with lower risks of all-cause death and HF rehospitalization, although RASi use was not significantly associated with adverse outcomes among patients with a lower eGFR [33]. Similar results have been reported for MRA use, as data from the GWTG-HF registry revealed that spironolactone was less frequently prescribed for HFrEF patients with advanced renal impairment (serum creatinine: 1.5–2.0 mg/dL) than for patients with serum creatinine concentrations of < 1.5 mg/dL [34]. Another report based on the OPTIMIZE-HF registry revealed that MRA use was associated with good clinical outcomes, even among older patients, if their eGFR was > 30 mL/min/1.73 m2 [35]. Ferreira et al. also evaluated MRA prescription patterns in a sub-analysis of data from RCTs and reported that lower MRA doses were prescribed to patients with chronic kidney disease [36]. This may be because these patients experience more frequent episodes of worsening renal function during MRA treatment, which necessitates close surveillance and dose adaptations. Nevertheless, patients still benefited at lower MRA doses. Clinicians must consider the risks and benefits of any specific treatment strategy, especially for patients with chronic kidney disease, who are frequently encountered in clinical practice.
Strengths and limitations
This study highlights the real-world challenges of HF management in malnourished patients, although it also has several inherent limitations. First, the retrospective observational nature is prone to bias and confounding by unmeasured or unidentified variables, although we adjusted the analyses for relevant clinical characteristics and tested different cut-offs as sensitivity analyses. Although well-designed RCTs would be needed to ensure the efficacy of GDMT, especially triple therapy, given the strength of the evidence for GDMT among non-malnourished patients, there may be ethical questions regarding testing these therapies against placebo in clinical trials. Also, the registry did not contain data regarding the specific doses of each agent, which precluded dose-related analyses. Future studies should evaluate whether malnourished patients benefit from lower drug doses. Finally, frailty can coexist with malnutrition, although we were unable to consider the relationship between these two conditions because of the lack of data regarding frailty.