Adherence to Treatment Guidelines in Ambulatory Heart Failure Patients with Reduced Ejection Fraction in a Latin-American Country: Observational Study of the Colombian Heart Failure Registry (RECOLFACA)

Abstract

Introduction

Although several guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) be treated with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) or angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitor (SGLT2i), there are still several gaps in their prescription and dosage in Colombia. This study aimed to describe the use patterns of HFrEF treatments in the Colombian Heart Failure Registry (RECOLFACA).

Methods

Patients with HFrEF enrolled in RECOLFACA during 2017–2019 were included. Heart failure (HF) medication prescription and daily dose were assessed using absolute numbers and proportions. Therapeutic schemes of patients treated by internal medicine specialists were compared with those treated by cardiologists.

Results

Out of 2,528 patients in the registry, 1,384 (54.7%) had HFrEF. Among those individuals, 88.9% were prescribed beta-blockers, 72.3% with ACEI/ARBs, 67.9% with MRAs, and 13.1% with ARNIs. Moreover, less than a third of the total patients reached the target doses recommended by the European HF guidelines. No significant differences in the therapeutic schemes or target doses were observed between patients treated by internal medicine specialists or cardiologists.

Conclusion

Prescription rates and target dose achievement are suboptimal in Colombia. Nevertheless, RECOLFACA had one of the highest prescription rates of beta-blockers and MRAs compared to some of the most recent HF registries. However, ARNIs remain underprescribed. Continuous registry updates can improve the identification of patients suitable for ARNI and SGLT2i therapy to promote their use in clinical practice.

Introduction

Heart failure (HF) represents a highly prevalent non-transmissible chronic disease worldwide, and it is considered one of the most relevant public health issues nowadays [1, 2]. This chronic condition is characterized by a high mortality and morbidity rate and a significant burden on the health systems [3]. Unfortunately, epidemiological analyses forecast a continuous increase in HF incidence in the upcoming years, highlighting the need to optimize strategies to mitigate its impact [4, 5].

In this context, several pharmacological and non-pharmacological therapies have effectively reduced the risk of several adverse events in HF, such as hospitalizations and death [6, 7]. Although most of this evidence is now supported by European guidelines and promoted by several scientific societies, incorporating these strategies into clinical practice still needs to be suboptimal, resulting in a vital heterogeneity when assessing the therapeutic approaches of HF patients in different centers [8]. To determine these interregional differences, several registries worldwide have evaluated adherence to the other HF treatment guidelines; nevertheless, no Latin-American registry has assessed this critical aspect [8–12]. This study aimed to characterize the pharmacological therapies of patients with HF in the Colombian Heart Failure Registry (RECOLFACA) and evaluate the proportion of those that received the medications and doses recommended by the HF guideline available to date of the registry. We also aimed to assess if there were differences in the prescription patterns between cardiologists and non-cardiologists.

Materials and Methods

Study Design and Population

The RECOLFACA is a prospective cohort study that includes 60 medical centers, HF clinics, or outpatient centers in Colombia. Specific inclusion and exclusion criteria and additional methodologic characteristics of the registry were described previously [13, 14]. Briefly, the enrollment began in February 2017 and included ambulatory patients over the age of 18 with a clinical diagnosis of HF of any etiology based on the guideline recommendations at the time of enrollment. Patients who have had at least one HF hospitalization in the 12 months prior to enrollment were also included. This study was approved by the Ethics Committee of the Fundación Valle del Lili under the act number 174-2017.

Data Collection

The information collected was registered at baseline and included sociodemographic, clinical, and laboratory variables. HF severity was categorized according to the New York Heart Association (NYHA) classification. Additionally, if the patient underwent a coronary revascularization procedure or had a previous myocardial infarction history, an ischemic disease diagnosis was registered. The comorbidities assessed were chronic kidney disease, arterial hypertension, atrial fibrillation, type 2 diabetes mellitus (T2DM), chronic obstructive pulmonary disease, thyroid disease, and dyslipidemia. In certain patients, additional echocardiographic variables, such as systolic diameter of the left ventricle and left ventricle ejection fraction, were available. We assessed the adherence to the therapeutic dosing regimens by dividing the cohort into three groups per medication: those receiving the optimal recommended dose, those receiving at least 50% of the recommended dose, and those receiving less than 50% of the amount recommended by the ESC guidelines [15, 16].

Statistical Analysis

Continuous variables were presented as medians and interquartile range, and categorical variables as absolute counts and proportions. All statistical analyses were performed using STATA version 15 (Station College, TX, USA). To identify differences between groups, we used Fisher’s exact, Pearson’s χ², and Mann-Whitney U tests depending on the type of variable for evaluation. A p value of <0.05 (two-tailed test) was considered statistically significant.

Results

The RECOLFACA cohort included 2,528 chronic and ambulatory HF patients between February 2017 and October 2019. From these, 1,384 had a diagnosis of HF with reduced ejection fraction (<40%) (HFrEF) and were included in the present analysis.

Population Characteristics

Table 1 summarizes the baseline characteristics of the patients enrolled in the RECOLFACA with a diagnosis of HFrEF. Most patients were males, and arterial hypertension, coronary artery disease, and T2DM were the most frequent comorbidities in this population. Moreover, around a third of the patients had an implantable device, with implantable cardioverter defibrillators being the most reported devices (Table 2).

Table 1.

Baseline characteristics of the patients with HFrEF enrolled in the Colombian Heart Failure Registry (RECOLFACA)

Variables	Total (N = 1,384), n (%)
Sex (male)	824 (59.5)
Age, median (IQR), years	68 (58, 76)
Population
European	59 (4.3)
Indigenous	5 (0.4)
Hispanic	988 (71.4)
Mestiza	283 (20.4)
African American	49 (3.5)
Comorbidities
Hypertension	957 (69.1)
Coronary artery disease	387 (28.0)
Dyslipidemia	357 (25.8)
T2DM	343 (24.8)
Atrial fibrillation	285 (20.6)
Smoking	256 (18.6)
Chronic kidney disease	248 (17.9)
Valvular disease	209 (15.1)
COPD	201 (14.5)
Thyroid disease	198 (14.3)
CABG	81 (5.9)
Chagas disease	54 (3.9)
Alcoholism	53 (3.8)
Cancer	49 (3.5)
Liver disease	5 (0.4)
NYHA classification
I	170 (12.3)
II	722 (52.2)
III	416 (30.1)
IV	76 (5.5)
ACC/AHA classification
C	1,294 (93.5)
D	90 (6.5)
SBP, median (IQR), mm Hg	118 (102, 130)
HR, median (IQR), bpm	72 (65, 82)
LVEF, median (IQR)	27 (20, 33)
NT-proBNP, median (IQR)	2,757 (985, 7,147)

COPD, chronic obstructive pulmonary disease; CABG, coronary artery bypass graft; SBP, systolic blood pressure; LVEF, left ventricle ejection fraction; NYHA, New York Heart Association; HR, heart rate; ACC/AHA, American Heart Association/American College of Cardiology; NT-proBNP, N terminal-pro-brain natriuretic peptide.

Table 2.

Summary of characteristic of patients based on ARNI prescription

Variables	Without ARNI (N = 1,203), n (%)	With ARNI (N = 181), n (%)	p value
Sex (male)	715 (59.4)	109 (60.2)	0.841
Age, median (IQR), years	68 (58, 76)	66 (58, 74)	0.099
Population			<0.001
European	40 (3.3)	19 (10.5)
Indigenous	5 (0.4)	0 (0.0)
Hispanic	865 (71.9)	123 (68.0)
Mestiza	252 (20.9)	31 (17.1)
African Americans	41 (3.4)	8 (4.4)
Comorbidities
Hypertension	825 (68.6)	132 (72.9)	0.498
Coronary heart disease	320 (26.6)	67 (37.0)	0.014
Dyslipidemia	305 (25.4)	52 (28.7)	0.621
T2DM	291 (24.2)	52 (28.7)	0.416
Atrial fibrillation	246 (20.4)	39 (21.5)	0.931
Chronic kidney disease	209 (17.4)	39 (21.5)	0.391
COPD	177 (14.7)	24 (13.3)	0.859
Thyroid disease	169 (14.0)	29 (16.0)	0.770
Valvular disease	168 (14.0)	41 (22.7)	0.010
CABG	71 (5.9)	10 (5.5)	0.964
Alcoholism	50 (4.2)	3 (1.7)	0.258
Chagas disease	49 (4.1)	5 (2.8)	0.685
Cancer	46 (3.8)	3 (1.7)	0.333
Liver failure	4 (0.3)	1 (0.6)	0.886
NYHA classification			0.766
I	144 (12.0)	26 (14.4)
II	633 (52.6)	89 (49.2)
III	360 (29.9)	56 (30.9)
IV	66 (5.5)	10 (5.5)
ACC/AHA classification			<0.001
C	1,135 (94.3)	159 (87.8)
D	68 (5.7)	22 (12.2)
Implantable devices			0.336
Dual-chamber pacemaker	38 (3.2)	6 (3.3)
Single-chamber pacemaker	16 (1.3)	5 (2.8)
ICD	254 (21.1)	44 (24.3)
CRT-P	31 (2.6)	2 (1.1)
CRT-D	77 (6.4)	13 (7.2)
SBP, median (IQR), mm Hg	118 (102, 130)	120 (100, 130)	0.889
HR, median (IQR), bpm	73 (66, 83)	70 (63, 78)	0.001
LVEF, median (IQR)	27 (20, 33)	28 (20, 32)	0.786
NT-proBNP, median (IQR)	2,760 (982, 7,669)	2,754 (985, 5,594)	0.761

COPD, chronic obstructive pulmonary disease; CABG, coronary artery bypass graft; SBP, systolic blood pressure; LVEF, left ventricle ejection fraction; ICD, implantable cardioverter defibrillator; CRT-P, cardiac resynchronization therapy pacemaker; CRT-D, cardiac resynchronization therapy defibrillator; NYHA, New York Heart Association; HR, heart rate; ACC/AHA, American Heart Association/American College of Cardiology; NT-proBNP, N terminal-pro-brain natriuretic peptide.

Pharmacological Therapy

At first, beta-adrenergic blockers were the most prescribed drug in the evaluated patients (88.9%, n = 1,231), followed by angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB) (72.3%, n = 1,000) and mineralocorticoid receptor antagonists (MRAs) (67.9%, n = 940). On the other hand, angiotensin receptor-neprilysin inhibitor (ARNI) was prescribed in 181 patients (13.1%). Patients prescribed with an ARNI had more frequent coronary heart disease and valvular disease. Furthermore, patients who received ARNI had a significantly lower heart rate compared to those who did not receive them; this is probably due to the central sympathetic suppression produced by ARNI which leads to a decrease in heart rate. Considering ACEIs, ARBs, and ARNIs, the combined prescription of these drugs reached 82.6% (n = 1,143). No significant differences in the prescription rates of any of these three medications were observed by specialist type (cardiologist vs. internal medicine specialist).

Regarding other drugs, ivabradine was prescribed in 118 (8.8%) patients, while digoxin in 172 (12.4%) and statins in 751 (54.3%). Finally, nitrates were reported in 57 (4.1%) patients, antiplatelets in 636 individuals (45.9%), and anticoagulants in 328 (n = 23.7%).

The geographical distribution of adherence to guideline recommendations by the pharmacological groups ACEI/ARBs/ARNIs, beta-blockers (BBs), and MRAs is shown in Figure 1. Finally, regarding the target dosages of these drugs, less than a third of the total evaluated patients reached the target doses recommended by the European HF guidelines (shown in Fig. 2). From these, ACEIs had the highest proportion of patients at target doses, followed by BBs. Furthermore, the proportion of patients receiving at least 50% of the target dose was the highest for MRAs, followed by ARBs.

Fig. 1.

Geographical distribution of adherence to guideline recommendations by pharmacological groups. a ACEI/ARBs/ARNIs. b BBs. c MRAs.

Fig. 2.

Adherence to target doses by different medications.

In Table 3, we summarize the main results of some of the most recently published HF registries worldwide.

Table 3.

Summary of recent HF registry-based studies evaluating pharmacological treatment

	QUALIFY International Registry	ESC HF Long-Term Registry (Spain)	CHECK-HF Registry	ASIAN-HF Registry	TSOC-HFrEF Registry	CHAMP-HF Registry	S-HFR	RECOLFACA
Patients*, N	6,669	1,526	5,701	5,276	1,509	3,518	36,274	1,384
Country	International	Spain	Netherlands	International	Taiwan	USA	Sweden	Colombia
Period, years	2013–2014	2012–2013	2013–2016	2012–2015	2013–2014	2015–2017	2003–2011	2017–2019
ACE/ARB	87%	92.6%	84%	77%	62.1%	73%	81%	72.3%
BBs	87%	93.3%	81%	79%	59.6%	67%	84%	89%
MRAs	69%	74.5%	56%	58%	49%	33%	29%	67.9%

*Total patients with HFrEF included in the registry.

Discussion

This study represents the first national estimation of adherence to international HF guidelines. These results comprehensively describe the prescription patterns for the main HF medications by region, highlighting a similar trend for patients treated by a cardiologist than those treated by an internal medicine specialist.

The percentage of patients with HFrEF receiving the recommended treatment varies among the published studies in the literature. From Table 3, we highlight a lower use of ACEI/ARBs in the RECOLFACA compared to almost all registries except the TSOC-HFrEF registry [17]. On the other hand, RECOLFACA showed one of the higher prescription rates of BBs than the other registries, surpassed only by the ESC HF Long-Term Registry in Spain [18]. Finally, MRA prescription in RECOLFACA was higher than most of the evaluated registries, with these medications being prescribed in more than two-thirds of the patients.

Observing a suboptimal dosage is also common in HF registries, reflecting a clear gap between the recommended doses and the actual “real-world” prescription schemes. The reasons behind these suboptimal prescriptions are multifactorial, highlighting adverse events of medications and the lack of experience of the treating physician, leading to clinical inertia [19, 20]. However, several studies have assessed the reasons for this lack of adherence to those medications and the limitations in reaching the recommended dosages, observing that a relevant clinical condition frequently precludes the up-titration process [21–23].

On the other hand, ARNI therapy was observed to be importantly underused, and this action was similar to the results of registry-based studies such as the CHAMP-HF registry (13%) but lower than that reported in the study of Smith et al. (27%) [24, 25]. Regarding the history of this medication, the US Food and Drug Administration (FDA) approved the ARNI sacubitril/valsartan (S/V) for patients with HFrEF in July 2015 after the important results of the PARADIGM-HF trial, in which S/V reduced the risk of cardiovascular death or hospitalization for HF in 20% compared to placebo [26]. As a result of this evidence, several clinical practice guidelines recommended using this medication for patients with HFrEF [15, 27]. Nevertheless, there have been substantial delays in the integration of these recommendations into clinical practice, as evidenced by the study of Luo et al. [28], which observed that only around 2% of patients with HFrEF without contraindications were prescribed ARNI therapy at hospital discharge, with prescription rates of even 0.13% in some hospitals. Nonetheless, they observed that S/V therapy at discharge increased gradually after the FDA approval [28]. It is relevant to highlight that the prevalence of patients with S/V therapy needs to be assessed in light of the population eligible for this treatment, which in some studies does not reach 30% of the total HFrEF population [29].

Similar to ARNIs, sodium-glucose cotransporter-2 inhibitor (SGLT2i) represented a revolutionary breakthrough in the setting of HF, achieving significant reductions in the risk of HF hospitalization and cardiovascular death in patients with HFrEF receiving optimal recommended therapy compared to placebo [30, 31]. Nevertheless, due to the FDA’s recent approval for patients with HF, few registries have estimated the prescription rates of these medications using real-life data [32], highlighting evident underuse despite approximately 4 of every 5 patients with HFrEF being possible candidates for initiation of an SGLT2i in the USA, according to the Get With the Guidelines-Heart Failure (GWTG-HF) Registry [33]. In this context, additional real-life data regarding the use of SGLT2i in patients with HF with and without T2DM are needed to evidence the significant potential for reducing health expenditures, morbidity, and mortality in these populations by promoting the prescription of these drugs in patients with HFrEF.

Finally, the observation of similar adherences to the recommended therapeutic schemes and dosages in patients treated by an internal medicine specialist compared to those treated by a cardiologist is similar to what has been reported in the literature [34–36]. In this setting, several studies have reported that HF medication up-titration is safe and efficient when performed by non-cardiologists [37]. One study showed that a nurse-led titration clinic under cardiologist supervision achieved the target BB doses in more than 80% of the treated patients [34]. These results improve adherence to therapeutic schemes and target doses in HF by encouraging non-cardiologists to be part of the HF drug optimization processes.

Study Limitations

First, participation in the registry was voluntary among participating sites; thus, selection biases could be present in the included sample. Second, as a cross-sectional analysis, assessing changes in treatment over time was impossible. Then, a critical limitation of this study was the lack of assessment of the potential causes of not prescribing or titrating the evaluated medications. Including data regarding adverse effects due to the medication and other contraindications would have allowed the estimation of the actual undertreatment prevalence. Finally, by the time the registry was actively recruiting, the ARNI had just been approved in Colombia by the National Institute of Drugs and Food Surveillance (INVIMA) for use in HFrEF, while the SGLT2i was not approved for use in HFrEF; therefore, we grouped ARNI with ACEI and ARB for analysis, but we could not estimate SGLT2i use as the RECOLFACA did not register data regarding antidiabetic medications.

Conclusions

Compliance related to the pharmacological recommendations of the 2021 European HF treatment guidelines on HFrEF patients in Colombia needs to be revised. Nevertheless, the adherence is comparable with those reported by other registries worldwide, highlighting one of the highest prescription rates of BBs and MRAs compared to some of the most recent HF registries. On the other hand, ARNIs remain importantly underprescribed, while there is no information regarding SGLT2i use in HFrEF patients in Colombia. These results highlight the importance of registries for assessing relevant aspects of real-life clinical practice and the need to improve the identification of patients suitable for ARNI and SGLT2i therapy to promote their use in clinical practice, also involving non-cardiologists in the process of pharmacological optimization in HF centers.

Statement of Ethics

This study protocol was reviewed and approved by the Biomedical Research Ethics Committee of the Fundación Valle del Lili, approval number 174-2017. Patient consent was not required in accordance with national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

No funding bodies had any role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Author Contributions

Alex Rivera-Toquica: investigation; methodology; supervision; and roles/writing – original draft, review, and editing. Luis Eduardo Echeverría: conceptualization; investigation; supervision; and roles/writing – original draft, review, and editing. Carlos Andrés Arias-Barrera, Fernán Mendoza-Beltrán, Diego Hernán Hoyos-Ballesteros, Carlos Andrés Plata-Mosquera, Juan Carlos Ortega-Madariaga, Juan Fernando Carvajal-Estupiñán, Viviana Quintero-Yepes, Luz Clemencia Zárate-Correal, Ángel Alberto García-Peña, Nelly Velásquez-López, and Claudia Victoria Anchique: investigation and writing – review and editing. Clara Saldarriaga: conceptualization; investigation; methodology; supervision; and roles/writing – original draft, review, and editing. Juan Esteban Gómez-Mesa: conceptualization; data curation; formal analysis; investigation; methodology; project administration; software; supervision; validation; visualization; and roles/writing – original draft, review, and editing.

Funding Statement

No funding bodies had any role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.