Characterization of 2,500 Patients with Heart Failure and Analysis of Their Optimal Medical Therapy: Insights from the AMERICCAASS Registry

Data Collection

The AMERICCAASS Registry included patients aged 18 and older (hospitalized or ambulatory) with a diagnosis of HF. Diagnosis of HF was based on information included in medical records that confirmed the diagnosis, and on receiving pharmacological treatment for this condition. The recruitment process began in April 2022 and concluded in November 2023, with a follow-up phase set to end in January 2025. A 12-month follow-up was planned for ambulatory patients, whereas 1-, 6-, and 12-month follow-ups were planned for hospitalized patients after discharge. Sociodemographic and clinical data were collected for each participant at the time of recruitment (ambulatory) or during hospital admission (hospitalized). Each participating medical institution was represented by a principal investigator and a sub-investigator who were responsible for entering data into the Research Electronic Data Capture (REDCap) electronic platform.

Statistical analysis

For this subanalysis, the first 2,500 patients included in the registry between 2022 and 2023 were considered. Descriptive statistics were primarily used. The normality of quantitative variables was determined using the Shapiro-Wilk test. Quantitative variables were reported as means and standard deviations (SD) if normally distributed or as medians and interquartile ranges (IQR) otherwise. Categorical variables were presented as absolute frequencies and percentages.

OMT was defined in patients with left ventricular ejection fraction (LVEF) ≤49% as those receiving quadruple therapy, including ACEI/ARB/ARNI, BB, MRA, and SGLT2i. Pharmacological treatment data were reviewed focusing on three specific quadruple therapy combinations. Other potential combinations were not evaluated.

Combinations included:

1. ACEI + BB + MRA + SGLT2i

2. ARB + BB + MRA + SGLT2i

3. ARNI + BB + MRA + SGLT2i

These therapies were analyzed in relation to LVEF according to the current HF classification: HFrEF (HF with reduced ejection fraction, LVEF ≤ 40%), HFmrEF (HF with mildly reduced ejection fraction, LVEF 41–49%), and HFpEF (HF with preserved ejection fraction, LVEF ≥ 50%) (18). The Chi-square test was used to assess the association between different pharmacological groups and LVEF categories. All analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria) and RStudio version 1.4.1717. A map of the Americas illustrating the participating countries was designed using MapChart.

Detailed information on the methodology employed in the registry, data management, statistical procedures, and bioethical considerations has been described previously (23).

Sociodemographic characteristics

The first 2,500 patients of the AMERICCAASS Registry were recruited from 82 medical institutions across 20 countries in the Americas (Argentina, Bolivia, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, the US, Uruguay, and Venezuela). Of these, 900 (36%) patients were hospitalized and 1,600 (64%) patients were ambulatory. Males accounted for 60.8% of hospitalized and 59.3% of ambulatory patients. The median age was 66.9 years for hospitalized patients (IQR 56.7, 77.1) and 66.3 years for ambulatory patients (IQR 56.5, 74.9). The predominant race in both groups was Mestizo (60.8% vs. 61.3%), followed by White (22.7% and 24.6%, respectively) (Figure 1).

Figure 1

Comorbidities and etiologies

Regarding comorbidities, most hospitalized patients had hypertension (HTN) (68.1%), dyslipidemia (38.1%), and diabetes mellitus (DM) (31.9%). Similarly, in ambulatory patients, hypertension (63.8%), dyslipidemia (45.3%) and DM (28.6%) were also highly prevalent. More than half of the patients had a body mass index (BMI) in the overweight or obese range (68.1% of hospitalized patients and 67.1% of ambulatory patients). Coronary artery disease (CAD) coexisted as a comorbidity in 31.6% of hospitalized and 37.5% of ambulatory patients (Table 1).

The main HF etiologies among hospitalized patients were ischemic (34.9%), hypertensive (17.3%), and valvular (12%). In ambulatory patients, ischemic (37.6%) and hypertensive (15.4%) were also the most common etiologies, followed by idiopathic (14.8%). Other etiologies, such as Chagas disease, tachycardiomyopathy, or viral, accounted for smaller percentages in both groups (Table 1).

Lifestyle

Most patients (71.6%) did not engage in physical exercise. Among those who exercised, 18.8% of hospitalized and 27.8% of ambulatory patients exercised 4–7 days per week. More than one-third of the patients had a history of smoking, with 38.3% of hospitalized and 37.8% of ambulatory patients, the majority being previous smokers in both groups (82.9% of hospitalized and 87.1% of ambulatory patients). Alcohol consumption was more common among hospitalized patients (29%) than ambulatory patients (25.5%). Among those who drank, hospitalized patients consumed alcohol more frequently, with 49.6% drinking one to two times per week, while 47.2% of ambulatory patients consumed alcohol occasionally or socially (Table 1).

Clinical characteristics

Most patients had a reduced LVEF, with 60.7% of the hospitalized group and 58.5% of the ambulatory group. The predominant NYHA functional class differed between the two populations: Class III was the most common among hospitalized patients (46.6%), while Class II was prevalent in ambulatory patients (56.9%). Hospitalized patients experienced high rates of dyspnea on exertion (84.6%) and at rest (72.2%), while ambulatory patients had dyspnea on exertion (62.9%) and lower limb edema (28.1%) as their predominant symptoms (Table 2).

Oral pharmacological treatment and OMT

At the time of hospital admission and recruitment, hospitalized patients were receiving the following medications (Table 3):

• BB (55.2%): mainly carvedilol (48.5%)

• MRA (38.9%): mainly spironolactone (93.4%)

• ARB (29.8%)/ACEI (18.8%)/ARNI (15.6%)

• SGLT2i (18.2%): mainly dapagliflozin (64%)

• Diuretics (51.6%): mainly furosemide (88.6%).

At the time of recruitment, ambulatory patients were receiving the following medications (Table 3):

• BB (71.4%): mainly carvedilol (43.7%)

• MRA (56.4%): mainly spironolactone (89.2%)

• ARB (26.8%)/ACEI (24.4%)/ARNI (26.8%)

• SGLT2i (34.2%): mainly dapagliflozin (64.5%)

• Diuretics (53.6%): mainly furosemide (81.2%)

For the analysis of OMT, of 2,500 patients, 1,978 had LVEF information. Among them, 334 (16.9%) were receiving quadruple therapy, with most distributed between HFrEF (246 patients, 73.7%) and HFmrEF (56 patients, 16.8%), while a smaller proportion fell into HFpEF (32 patients, 9.6%) (Table 4).

• When analyzing quadruple therapy use within each HF subtype, 21% of all patients with HFrEF, 12.3% of all patients with HFmrEF, and 9% of all patients with HFpEF received it.

• The most frequent therapy included ARNI plus BB/MRA/SGLT2i in the overall analysis (72.5%). This was predominantly observed in patients with HFrEF (75.2%), and to a lesser extent in those with HFmrEF (69.6%) and HFpEF (56.3%). Despite those lower percentages, this combination remained the most prevalent therapy in the other two groups (HFmrEF and HFpEF).

• The therapy that included ARB plus BB/MRA/SGLT2i was the second most prevalent in the overall analysis (15.3%). It was mainly used in patients with HFpEF (40.6%) and HFmrEF (16.1%) and to a lesser extent in patients with HFrEF (11.8%).

• The combination that included ACEI plus BB/MRA/SGLT2i was the third most prevalent or least used OMT combination in the overall analysis (12.3%). It was more prevalent in HFmrEF (14.3%) and HFrEF (13%) than in HFpEF (3.1%).

Sociodemographic characteristics

The predominance of male sex and Mestizo race, along with the reported mean ages, reflects the demographic behavior of HF in the nations studied. Globally, the age-standardized prevalence of HF is similar between sexes, although slightly higher in males (24, 25). The incidence, on the other hand, is lower in females, especially in HFrEF (25). The findings of this study align with these trends, mirroring international data. These sex-based differences may be attributed to the distribution of cardiovascular risk factors between men and women (26, 27).

Traditionally, HF has been associated with older age groups. A 2022 systematic review reported a higher prevalence in patients aged over 50 years (28). Similarly, the PULSE study reported a mean age of 75 years for HF patients and a higher incidence among those aged over 85 years (29). The findings of this study show median ages over 60 years for both hospitalized and ambulatory groups, which are consistent with scientific evidence and global trends. However, recent European studies show a rising incidence of HF in patients under 50 years, attributed to modifiable risk factors, such as obesity and smoking (30, 31, 32, 33). This trend underscores the need for targeted prevention and management strategies for younger patients.

Comorbidities and etiologies

Our findings show a significant prevalence of comorbidities, including HTN, dyslipidemia, CAD, and DM, in both hospitalized and ambulatory HF patients. Ischemic and hypertensive etiologies were identified as the main causes of HF in both groups. This is consistent with current scientific evidence that highlights these conditions among the leading predisposing factors for HF (25). The INTER-CHF study reported high rates of HTN (73.6%), dyslipidemia (48.7%), DM (21.9%), and myocardial infarction (18.3%) among South American HF patients. The same study found that ischemic (25%) and hypertensive (21%) were the predominant etiologies of HF in this region (16, 25). Similarly, the REPORT-HF study found HTN (68%) to be the most common comorbidity, with CAD (33%) and type 2 diabetes (31%) also being prevalent in Central and South America. This study also found that ischemic and hypertensive etiologies were the leading causes of HF in the Americas (34). Both studies reported high frequencies of these etiologies and comorbidities on a global scale (16, 34). The high prevalence of these conditions underscores the need for a comprehensive strategy to optimize HF management by addressing key comorbidities.

Our study also identified a high proportion of overweight and obese patients, consistent with the existing evidence. The REPORT-HF study reported a median BMI in the overweight range and a 10% prevalence of obesity in patients from Central and South America, which was lower than 49% prevalence reported from North American populations (34). Similarly, the INTER-CHF study found a mean BMI in the overweight range for the HF patients from South America, with comparable results in other regions (16). These findings emphasize the need for comprehensive patient management, including effective weight control strategies.

Lifestyle

Our findings reveal a higher prevalence of unhealthy habits among HF patients, characterized by low levels of physical activity and high rates of smoking and alcohol consumption, consistent with scientific literature. Sedlar et al. observed low adherence to exercise (39%), primarily related to a lack of self-care knowledge (35). Smoking and alcohol consumption, recognized risk factors for cardiovascular diseases, are strongly associated with higher HF incidences and hospitalization rates in these patients (36, 37, 38). For instance, a study involving 989,080 hospitalized HF patients found that 15% had substance use disorders: 12.1% related to tobacco and 3.5% to alcohol. The highest prevalence was observed in those aged 45 to 55, potentially correlating with the rising incidence of HF in younger populations (39). The INTER-CHF study also demonstrated higher rates of tobacco and alcohol consumption in Latin America compared with other territories (16).

The observations from the AMERICCAASS cohort and related studies suggest suboptimal adherence to non-pharmacological recommendations for HF management, highlighting key intervention areas across North, Central and South America. Targeted education and structured programs, such as smoking cessation, alcohol reduction, and supervised exercise, could enhance adherence and improve quality of life and health outcomes, as habits like regular exercise have been shown to reduce hospitalization and mortality in HF patients (40).

Clinical characteristics

The results of this study show a predominance of NYHA classes II and III in ambulatory and hospitalized patients, respectively. Additionally, most patients had HFrEF, regardless of their status. These findings reflect the severity of HF in the Americas and align with existing literature. The INTER-CHF study reported similar trends in South America, Africa, Asia, and the Middle East (16). The REPORT-HF study also found a predominance of NYHA class II and III patients in all the regions evaluated, including Central and South America. The same study revealed a high prevalence of patients with HFrEF globally, accounting for 50% of the studied population (34). However, this contrasts with studies such as I PREFER, which reported a higher prevalence of patients with LVEF (>45%) in Latin America, associated with a predominance of NYHA classes other than III/IV (70%) (41).

Oral pharmacological treatment and OMT

The percentage use of BBs, MRAs, ARBs/ACEI/ARNI, and SGLT2i in the AMERICCAASS Registry demonstrates alignment with current scientific evidence, which supports the use of these pharmacological groups in combination based on LVEF (19). However, the use of SGLT2i and MRAs is lower compared with the other pharmacological groups, highlighting the need for targeted strategies to increase their uptake in eligible patients.

The evaluation of pharmacological combinations also reveals a trend in management that aligns with current clinical practice recommendations, as quadruple therapy was primarily observed in patients with HFrEF (73.7%) and HFmrEF (16.8%). Its prescription for patients with HFrEF is widely recommended in the leading HF guidelines, which advocate for a foundational approach in treating this subpopulation, with a preference for ARNI over ARBs and ACEI, as observed in previous results (18, 19, 42, 43). In patients with HFmrEF, a significant use of quadruple therapy was observed, with a preference for management with ARNI. Although the scientific evidence is less robust, it suggests a potential benefit of this therapy in this subgroup of patients, particularly in terms of mortality and hospitalizations (43).

Quadruple therapy was less commonly used among patients with HFpEF, reflecting the individualized treatment approaches recommended by clinical guidelines. However, 9.6% of the overall use of quadruple therapy was observed in this group, and 9% of all HFpEF patients received such treatment, particularly ARB-based combinations, possibly deviating from clinical recommendations. In this subgroup, the prescription of SGLT2i is prioritized, as it is the pharmacological group with the highest level of evidence (43). Nonetheless, recent studies suggest a potential benefit of MRAs and ARNI in this population, which may justify their prescription. These recommendations, however, only apply to patients with LVEF lower than 60% (44). Moreover, the recent FINESART-HF trial demonstrated that finerenone significantly reduces the rate of composite outcomes, including worsening HF events and cardiovascular mortality, in patients with HFmrEF and HFpEF. While the data used in this study precedes these findings, this recent evidence could bolster their relevance and could highlight the potential application of MRAs in clinical practice (45, 46). By contrast, the evidence regarding the use of BBs in this group is more limited and does not indicate clear benefits (43). This discrepancy may suggest deviations from current clinical guidelines, although further research is necessary to draw definitive conclusions.

While the findings of this study on prescribing patterns partially align with current recommendations, adherence to OMT remains low, with only 21% of patients with HFrEF receiving guideline-recommended management. These results, however, are higher than some existing reports that evaluate adherence to OMT, which show very low usage rates. Anderson et al., for example, found that approximately 1% of patients in this subgroup receive the recommended pharmacological management (47). In contrast, the CHAMP-HF Registry found a 22.1% usage rate of ARBs/ACEI/ARNI, BBs, and MRAs, although only 1% of patients were receiving this management at optimal doses (47, 48). Another study found that 18% of their HF patients in cardiac rehabilitation were receiving OMT (49). Similarly, the findings of this study for HFmrEF showed a low usage of OMT, with only 12.3% receiving quadruple therapy.

These findings demonstrate that initiating and adhering to OMT are a healthcare challenge, especially in low- and middle-income countries (50). The minimal increases in utilization rates between the years 2013 and 2019 reflect this issue (51). Multiple barriers contribute to these difficulties, including clinical factors such as early discharge pressure, misunderstanding of therapy by patients, and knowledge gaps on evidence-based recommendations by physicians (50, 52). Moreover, advances in medical knowledge may outpace the ability of healthcare systems to implement them. Additionally, the underrepresentation of certain populations in clinical trials may potentially impact adherence, as inclusion criteria may differ from real-world practice. However, this is unlikely to fully explain the substantial gaps in OMT application, as inclusion criteria are typically fundamental eligibility requirements (53).

Economic factors, especially limited access to healthcare and lack of health insurance, also play a role in these dynamics (50, 52). Patient costs, particularly prescription copayments, may impact the implementation of OMT (53). Additionally, social disparities regarding sex or ethnicity may affect the prescription of certain pharmacological groups, further hindering OMT implementation. For instance, the CHAMP-HF Registry found that women and Hispanic patients were less likely to receive ACEI, ARBs, and ARNI than other groups (48, 50, 54).

Although implementing OMT presents several challenges, various strategies, such as educational sessions, reminder systems, self-care support initiatives, and telemonitoring, have been studied for their effectiveness in improving OMT adherence in HF. A meta-analysis of 55 randomized controlled trials found that adherence-enhancing strategies increased adherence by 10%. Interestingly, 31 trials demonstrated their effectiveness in promoting lifestyle modifications, reinforcing the need to address poor adherence to non-pharmacological recommendations, as highlighted in previous findings (55). Notably, these interventions have also been shown to reduce mortality and hospitalizations, strengthening their clinical importance (55, 56). Finally, digital interventions that collect data beyond structured care episodes could help to optimize pharmacological therapy in these patients; however, further research is needed (57).