Heart failure (HF) is a chronic condition that poses a significant challenge for healthcare.1 In developed countries, the prevalence of HF is estimated to be between 1% and 2% of the general adult population.2 Studies conducted in the Portuguese population indicate a higher prevalence. EPICA,3 a community-based epidemiological study conducted over 25 years ago with subjects over 25 years attending primary care units, estimated an overall prevalence of HF of 4.36%. Recently, the PORTHOS4 study showed an overall estimated HF prevalence of 16.54% in community-dwelling individuals aged 50 years or older. In both studies, HF with preserved ejection fraction (HFpEF) was the most common HF phenotype, while HF with reduced and mildly reduced ejection fraction (HFrEF) estimated prevalence was 1.3% in both EPICA (ejection fraction <45%) and PORTHOS (ejection fraction <50%). The estimated prevalence of HFrEF in the PORTHOS study was 0.35%. Although the increase in overall HF prevalence is driven by HFpEF, managing HFrEF continues to pose significant challenges.5

The health costs of HF are expected to increase in the coming years.6–8 Gouveia et al. estimated that, in 2014, HF direct costs (hospitalizations, medications, diagnostic and therapeutic procedures, medical appointments, and emergency and long-term care) in Portugal amounted to €299 million, with indirect costs (employment-related) totaling €106 million.9 By 2036, total costs were projected to rise from €405 million to €503 million.8

Both cardiac and non-cardiac comorbidities are prevalent among patients with HF. HFrEF presents a grim outlook as patients are at a high risk of disease progression, worsening symptoms, hospitalization, and death.10 Despite advancements in HF treatments, mortality remains high. The European Society of Cardiology (ESC) Heart Failure Long-Term Registry reports 1-year mortality of 23% for acute HF and 6% for chronic HF.11 Furthermore, patients with HF experience a variety of symptoms that significantly impair their quality of life and daily activities.12

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) were initially developed to treat type 2 diabetes mellitus (T2DM). However, during clinical trials, researchers observed a significant reduction in HF hospitalizations among patients with T2DM taking SGLT2i.13 The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study then evaluated the efficacy and safety of dapagliflozin in patients with HFrEF regardless of the presence of T2DM. Notably, dapagliflozin was well-tolerated, with no significant difference in safety events compared to placebo.10 Beyond its impact on mortality and hospitalization, dapagliflozin also improved symptoms, physical function, and quality of life on top of optimization of HF treatment.10,14 Based on the robust efficacy and safety profile demonstrated in DAPA-HF,10 dapagliflozin was recommended to reduce mortality and morbidity in HFrEF patients.15

However, like most clinical trials, the DAPA-HF study had specific eligibility criteria, which limits its external validity for a broader population. Therefore, it was important to explore real-world data (RWD), to analyze the population under dapagliflozin treatment for HFrEF in a real-world clinical setting.10

EVOLUTION-HF sought to characterize patients who initiated dapagliflozin for HFrEF treatment and to provide early insights regarding real-world dapagliflozin treatment patterns.

The EVOLUTION-HF study aimed to characterize patients with HFrEF who initiated treatment with dapagliflozin in a real-world setting in Portugal. Our findings indicate that the majority of patients in our study are young males who exhibit mild HF symptoms, with dyslipidemia (59%) and hypertension (56%) being the most prevalent comorbidities. The results indicate a high utilization of guideline directed medical therapy (GDMT) for HFrEF at baseline: 92% received betablockers, 71% were on MRAs, and 55% on ARNIs. Most patients (95%) adhered to dapagliflozin treatment, and there was an increase in the prescription and/or dosage adjustment of beta-blockers, mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor-neprilysin inhibitors (ARNI). In contrast, loop diuretics and ACE inhibitors were reduced or discontinued during the 12-month period. This is the first study, to our knowledge, that characterizes a real-world cohort of HFrEF patients treated with dapagliflozin across various regions of Portugal.

The high adherence to dapagliflozin suggests that it is well tolerated; in fact, only 2% of those who stopped taking the medication did so due to adverse events. We were unable to carry out the planned analysis of the factors influencing the discontinuation of dapagliflozin due to the small number of cases.

Compared to contemporary trials including HFrEF patients, the cohort from EVOLUTION-HF presented a high level of GDMT use at index date, according to the 2021 ESC HF Guidelines.16 Data from Registries show a much lower level of HF GDMT implementation.17,18

By comparing clinical characteristics and treatment patterns of patients included in the DAPA-HF randomized trial10 and the EVOLUTION-HF study, similar characteristics in terms of age, sex, mean LVEF, and baseline eGFR were observed. Notwithstanding, it is worth mentioning that patients in the EVOLUTION-HF study tend to have a higher percentage of NYHA II (85% vs 68%) and lower median NT-proBNP value (920 vs. 1428 pg/mL) in comparison with DAPA-HF. Additionally, lower comorbidities in this study when comparing to DAPA-HF, such as CKD (8% vs 41%, respectively), might reflect a tendency to initiate dapagliflozin in patients with less burden of comorbidities, as these were the first subset of HF patients being treated with the drug. Regarding treatment patterns, the EVOLUTION-HF study showed a tendency for higher use of ARNI and lower use of diuretics at the index date. These differences can be attributed to the time elapsed between the DAPA-HF read-out date (March 2019), the update of HF guidelines,16 and inclusion of patients in EVOLUTION-HF. This indicates the gradual integration of evidence and updated guidelines into clinical practice, particularly concerning the use of ARNI.

The higher level of prescription and/or up-titration of betablockers, MRAs, and ARNI after dapagliflozin initiation, while loop diuretics and ACE inhibitors were down-titrated/withdrawn, aligns with findings from other studies suggesting that dapagliflozin initiation may facilitate a better optimization of GDMT.19,20 One of the reasons for such an effect might be that dapagliflozin is associated with a lower risk of hyperkalemia, an adverse event responsible for the down-titration/discontinuation of MRA or ARNIs. Moreover, we can argue that dapagliflozin's effect on the cardiac cell20,21 allows for a more favorable cardiac environment which might grant the opportunity for enhanced therapeutic benefits, although further randomized research is warranted. It is also important to note that the 2021 ESC HF Guidelines16 advise for a more aggressive treatment regimen, where the four pillars of GDMT (iECA/ARA or ARNI, betablockers, MRA, and SGLT2) should be introduced as soon as possible – EVOLUTION-HF's results might again be reflecting the gradual integration of said guidelines into clinical practice throughout the duration of the study.

This study has some limitations. It is important to acknowledge the site selection bias, since participating sites were chosen for their expertise in HFrEF management and are not representative of HF clinical practice in Portugal. Nevertheless, it was not an aim of the EVOLUTION-HF study to fully capture the Portuguese clinical practice, but to analyze the first real-world experiences of dapagliflozin use in this new setting of patients. Since the study relied on existing medical records, data collection was limited by the information documented for each patient. Another relevant aspect to consider is that real-world HFrEF populations may differ depending on the clinical setting in which they are managed. While our study was conducted exclusively in Cardiology departments and ambulatory patients, other settings, such as Internal Medicine departments, might exhibit different patients’ baseline characteristics, comorbidity burdens, and treatment patterns. Although our study was not designed to capture these broader patient groups, future research including more diverse clinical settings could provide further insights into the generalizability of our findings across different real-world HFrEF populations.

There are important strengths to acknowledge as well. While not representative of all Portuguese HF care, this is a multicentric study and patients were recruited from distinct geographic locations (north to south) and various hospital settings (university to regional hospitals). Finally, this Portuguese EVOLUTION-HF cohort will be integrated with a multicountry study. By combining data across countries, researchers can gain a clearer understanding of global treatment patterns and clinical characteristics of HFrEF patients receiving dapagliflozin in real-world practice.

The results of this study confirm, in a real-world setting, the favorable safety profile of dapagliflozin that was previously reported in clinical trials, with the therapeutic levels of dapagliflozin maintained in 95% of patients. Despite a high use of HF GDMT at baseline, an increase in prescriptions and/or up-titration for betablockers, MRAs, and ARNIs was observed, alongside a decrease in the use of loop diuretics and ACEi throughout the study.

Central picture legend: Intake of HFrEF medications throughout the study. (A) At index date. (B) Changes at follow-up (These numbers refer to the number of changes, not changes per patient. This means that when there are 44 dose increases in beta-blockers, for example, there may have been 2 increases in one patient. It does not mean that 44 participants had changes. What we do know is the number of beta blockers that existed at baseline (n=160), and we know that there were 44 increases.) ACE: angiotensin-converting enzyme; ARB: angiotensin; ARNI: angiotensin receptor-neprilysin inhibitor; CV: cardiovascular; HRrEF: heart failure with reduced ejection fraction; MRA: aldosterone antagonist.

Central message: Despite the high use of GDMT at dapagliflozin initiation, an optimization of HFrEF therapy was observed during the 12-month follow-up period.

The authors have no conflicts of interest to declare.