This was a real-world study involving patients with HF who were treated at the Affiliated Hospital of North Sichuan Medical College (Nanchong, China) from July 2017 to June 2021. Inclusion criteria included meeting the diagnostic and treatment standards for HFrEF in the “Chinese HF Diagnosis and Treatment Guidelines 2018”, follow-up for at least 6 months, receiving inpatient or outpatient care at the hospital, $\ge$18 years old with chronic HF, and diagnosed with left ventricular EF $\le$40% (on the most recent echocardiogram, $\le$2 years). The study excluded patients with follow-up less than half a year and patients with missing follow-up data, malignant tumors or other fatal diseases, had a history of major cardiac therapy such as heart transplantation or left ventricular assist device implantation, or had history of acute HF. All patients were divided into high compliance, moderate compliance, and low compliance with GDMT groups. The study analyzed the proportion of patients receiving treatment in compliance with GDMT, evaluated the relationship between compliance with GDMT and clinical outcomes, and identified the risk factors of low compliance. The study was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College, and since the study only involved a retrospective analysis of previous clinical data, the requirement for informed consent was waived.

The data used in this study were extracted from a database constructed by combining information from multiple data sources including the Hospital Information System, Laboratory Information Management System, Picture archiving and Communication Systems, and Electronic Medical Record of the Affiliated Hospital of North Sichuan Medical College. The variables of interest in this study included patients’ sociodemographic information, drinking history, smoking history, previous medical history, comorbidities, HF-related characteristics, New York Heart Association (NYHA) functional class, laboratory parameters, medication, and other treatments.

Compliance with guideline score was based on physicians’ compliance with the latest European Society of Cardiology (ESC) HF guideline recommendations at the time the study registry was established [21]. Scores were related to the following five classes of medications recommended by the ESC: ACEI, ARB (if ACEI was not tolerated), ARNI, BB (it is recommended that all patients with HFrEF be prescribed an ACEI [or ARB or ARNI] and BB, except in cases of contraindications or intolerance), MRA (I. Patients with HFrEF NYHA class II–IV with EF $\le$35% who remained symptomatic, although already on an ACEI [or ARB or ARNI] and BBs; II. All patients after an acute myocardial infarction who had an EF $\le$40% with symptoms of HF or who had diabetes mellitus [DM]), and ivabradine (sinus rhythm, heart rate $\ge$70 bpm, NYHA class II–III, who were already receiving GDMT, including BBs at the maximum tolerated dose).

The compliance score was the ratio of treatment actually prescribed to what should theoretically have been prescribed. The treatment score was calculated for every drug for every patient prescribed, taking into account treatment eligibility criteria, guideline-based contraindications to drugs, side effects of the drug, and intolerance to the drug documented. The score was calculated for each patient by summing the points as follows: 0 points for non-prescription in the absence of contraindications and 1 point for the use of medicine; non-administration of the recommended drugs because of specific contraindications or intolerance was scored as compliance with guidelines. The total score ranged from 0 (very poor) to 1 (good) and we defined three levels of compliance: good compliance (score = 1), moderate compliance (score $>$0.5 to $\le$0.75), and poor compliance (score $\le$0.5). In this study, the term “compliance” only related to physicians’ compliance with guidelines and not to patients’ adherence or persistence.

Continuous variables were checked for normality by using the Kolmogorov–Smirnov test. The normally distributed continuous variables are presented as the mean $\pm$ standard deviation, and the skewed distributed continuous variables are presented as the median and interquartile range (IQR). Categorical variables are displayed as the number and percentage. Comparisons of variables among the three groups were determined by one-way analysis of variance, the Kruskal-Wallis test, or the chi-square test. Factors with p 0.05 in the comparison analysis were further analyzed using multivariate ordinal logistic regression to screen the independent influencing factors of physicians’ guideline compliance. All statistical analyses were performed using R software (version 4.2.0, Lucent Technologies, Murray Hill, NJ, USA), and the threshold of statistical significance was p 0.05.

A total of 2096 patients with HF were included in this study, with an average age of 69.5 $\pm$ 11.0 years, most of whom were male (58.7%). Among these patients, there were 185, 1413, and 498 patients in the high, moderate, and low compliance with GDMT groups, respectively. Comparisons among groups of the baseline characteristics showed significant differences in hypertension (p = 0.048), renal insufficiency (p 0.001), and history of cardiac resynchronization therapy (CRT) (p 0.001). There were no significant differences in the other variables among the three groups (Table 1).

Our study found that 767 (36.59%) HF patients received ACEI/ARB/ARNI treatment, 1684 (80.34%) HF patients received beta blocker treatment, 1492 (71.18%) HF patients received ivabradine treatment, and 1614 (77.00%) HF patients received MRA treatment in compliance with GDMT (Fig. 1). Of all patients with HF included in the study, 498 (23.8%) had low compliance with GDMT, 1413 (67.4%) had moderate compliance with GDMT, and 185 (8.8%) had high compliance with GDMT (Fig. 2).

Fig. 1.

Proportion of patients with HF receiving different drugs in compliance with GDMT. HF, heart failure; GDMT, guideline-directed medical therapy; ACEI, angiotensin-converting enzyme inhibitor; ARBs, angiotensin-receptor blockers; ARNI, angiotensin-receptor-neprilysin inhibitor; MRAs, mineralocorticoid receptor antagonists.

Fig. 2.

Physicians’ guideline compliance.

The effect of compliance with treatment guidelines on clinical outcomes was analyzed. The readmission rate of patients in the moderate compliance with GDMT group was significantly higher than that in the high and low compliance with GDMT groups (p = 0.028; Fig. 3A). There were no significant differences in severe cardiovascular disease (CVD) rate among the low, moderate, and high compliance with GDMT groups (p = 0.569; Fig. 3B). Interestingly, patients in the high compliance with GDMT group had significantly higher mortality rates than those in the low and moderate compliance with GDMT groups (p 0.001; Fig. 3C).

Fig. 3.

Correlation of clinical outcomes with physicians’ guideline compliance. (A) The correlation of readmission with physicians’ guideline adherence; (B) The correlation of severe CVD rate with physicians’ guideline adherence; (C) The correlation of mortality with physicians’ guideline adherence. CVD, cardiovascular disease.

There were significant differences in heart rate (p 0.001), diastolic blood pressure (DBP) (p = 0.030), systolic blood pressure (SBP) (p = 0.007), creatinine kinase MB (CK-MB) (p 0.001), high-sensitive troponin T (hsTnT) (p 0.001), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (p 0.001), uric acid (p 0.001), estimated glomerular filtration rate (eGFR) (p 0.001), urea nitrogen (p 0.001), serum creatinine (p 0.001), alanine aminotransferase (ALT) (p = 0.046), aspartate aminotransferase (AST) (p 0.001), alkaline phosphatase (ALP) (p = 0.028), gamma-glutamyl transpeptidase (GGT) (p 0.001), total protein (p = 0.024), albumin (p 0.001), prothrombin time (p = 0.001), fibrinogen (p = 0.011), red blood cells (p = 0.032), Free Triiodothyronine (FT3) (p 0.001), Free Thyroxine (FT4) (p 0.001), and left ventricular diastolic dysfunction (LVDD) (p 0.001) among the three groups. There were no significant differences in other laboratory indexes among the three groups (Table 2).

Ordinal logistic regression results showed that a history of hypertension (odds ratio [OR] = 1.332, 95% confidence interval [CI]: 1.090–1.628; p = 0.005); NYHA classification (III vs. I) (OR = 1.569, 95% CI: 1.168–2.111; p = 0.003); NYHA classification (IV vs. I) (OR = 1.874, 95% CI: 1.180–2.974; p = 0.008); and abnormal heart rate (OR = 1.627, 95% CI: 1.312–2.021; p 0.001), hsTnT (OR = 1.398, 95% CI: 1.104–1.771; p = 0.005), NT-proBNP (OR = 1.472, 95% CI: 1.150–1.886; p = 0.002), uric acid (OR = 1.398, 95% CI: 1.128–1.734; p = 0.002), and LVDD (OR = 1.358, 95% CI: 1.094–1.686; p = 0.006) were all significantly associated with low compliance with GDMT (Table 3).

This study conducted stratified analysis on patients with HF with different NYHA scores and compared the impact of guideline compliance on clinical outcomes in these patients. In patients with I/II NYHA, there were significant differences in readmission rates (p = 0.033) and mortality rates (p = 0.001) among the high, moderate, and low compliance with GDMT groups. There were no significant differences in severe CVD rates (p = 0.913) among the three groups. In patients with III/IV NYHA, there were no significant differences in readmission rates (p = 0.317), mortality rates (p = 0.766), and severe CVD rates (p = 0.725) among the three groups (Table 4). This study also compared the influence of basic characteristics and laboratory index of patients with I/II NYHA on physicians’ compliance with guidelines. The results are shown in Supplementary Tables 1,2.

Our research describes in detail the clinical profile of our patients, who had a mean age of 69.5 years, tended to be older than those reported in previous studies, had an SBP of 145 mmHg, and had higher rates of common comorbidities including hypertension (57.3%) and DM (26.6%). Compared with the ASIAN-HF registry [22], device use was low in our study, with only 0.3% using an implantable cardioverter defibrillator and 0.1% undergoing CRT; this discrepancy may be partly related to socioeconomic considerations.

There is clear evidence from drug research studies showing that drugs recommended by the guidelines improve the clinical outcome of HF patients [23, 24]; however, there is still a large gap between GDMT and clinical practice [22, 25, 26]. We found that physicians’ compliance score was good in 8.8%, moderate in 67.4%, and low in 23.8% of patients, which was significantly lower than the QUALIFY global survey in which adherence was good in 67%, moderate in 25% and poor in 8% of patients [27]. Thus, in our study, there were still a large number of patients who received unoptimized treatment with just one or two of these medications, opposed to combination therapy, as recommended by guidelines, and only 8% of the patients received optimized treatment. Among eligible candidates with HFrEF, physicians tended to be in relative moderate compliance with BBs (80.3%) and MRAs (77%), similar to that of European countries; and in poor compliance with ACEI /ARB/ARNI (added up to 36.6%), which was much lower than that of European countries [12, 26, 28, 29] and the China PEACE Retrospective acute myocardial infarction (AMI) Study [30]. The high rate of use of MRAs in our study could be attributed to a nationwide quality assessment evaluation program [31] and the low cost of MRA. Poor compliance with ACEI was presumably due, in part, to the higher prevalence of persistent cough resulting from ACEI [32]. Contraindication to severe chronic kidney disease or renal failure also plays an important role. However, physicians’ awareness, including concern of adverse effects after combination therapy or during dose escalation for older patients, and economic factors also affecting physicians’ compliance level.

Although previous studies have encouraged uptitration, underdosing still remained significant in our study. A substantial proportion of patients with HFrEF received doses considerably below the guideline-recommended doses, especially for BBs. In view of this situation, the Chinese guidelines emphasize that BBs should gradually reach the target dose or maximum tolerance to facilitate clinical implementation, which lowers resting heart rate to 60 beats$\cdot$min${}^{-1}$ [33]. Studies have proven that Asians achieve similar benefits as Westerners at lower statin doses [34, 35]. In addition to the low body mass index, complexities of the heterogeneous populations [36] and the heightened drug sensitivity of Asians, together with the pharmacokinetic variability [34, 35], may explain why prescribed doses were lower for patients in our study than western populations.

Data on the impact of physicians’ compliance with GDMT on clinical outcomes in daily practice are limited, particularly in China. We evaluated the physicians’ compliance with GDMT as well as the relationship between guideline compliance and clinical outcomes in hospitalized and outpatients with HFrEF in China for the first time. We found that high compliance with treatment guidelines was independently correlated with the low rate of HF or CVD rehospitalization, consistent with other studies [22, 37]. By contrast, we observed no significant benefit on mortality, which was inconsistent with another study [38]. Interestingly, we also found that physicians’ compliance was related to mortality in patients with NYHA I/II but not in patients with NYHA III/IV. To explore additional reasons, we conducted a subgroup analysis, which showed that in the group of patients with NYHA I/II, higher mortality was strongly correlated with comorbidities such as hypertension and renal insufficiency. The possibility that compliance had less impact on mortality than on hospitalization may be explained by the fact that mortality for HF is likely to be affected by several medical and non-medical factors including characteristics of the population baseline in our study, such as higher co-morbidities, older age, frailty, and poor financial situation. It is all the more interesting that aggressive treatment is often for patients in the more severe NYHA functional class in order to provide symptom relief. Thus, in our study, physicians’ compliance was better in patients with NYHA I/II with higher mortality risk but not in patients with NYHA III/IV. These findings are in accordance with the previously described “risk-treatment paradox”, where HF patients with the greatest need are less likely to receive appropriate therapy [39]. As quality improvement programs including improving the health care system and medical insurance systems, or a series of physician professional level training programs have been developed over the past years to improve the daily care of patients with HF in China, an increasing number of patients with HFrEF have been treated GDMT. With the increased demand to improve the quality of medical care in China, more efforts are needed to perform improvement measures and optimize the quality of data-based digital management systems, which have been shown to be efficient.