Management of Heart Failure in a Resource-Limited Setting: Expert Opinion from India

Panel discussion A detailed physical examination and strong clinical suspicion are core for diagnosing HF in a resource-limited setting. Abnormal ECG and chest X-ray showing cardiomegaly and congestion are indicators of HF. NT-proBNP and 2D echocardiography (2D echo) imaging are essential tests for diagnosing and phenotyping HF. Diagnosing HFpEF is more challenging compared to HFrEF. Assessment of diastolic function in 2D echo shall be done to diagnose HFpEF. The H₂FPEF scoring system could be helpful in such clinical situations. The chances of HFpEF are high in elderly patients with atrial fibrillation (AF), hypertension, and obesity. The use of modified stress diastology, such as the 6-min walk test, E/e′ ratio, and mitral velocities, are a few additional tests that aid in diagnosing HFpEF. Thus, for diagnosis, the clinical acumen of a primary physician is essential. For diagnosing HFpEF, the cardiologist’s expertise in diastology is crucial for correct diagnosis. Also, available resources for diagnosis are to be considered. In resource-limited settings where access to advanced investigations and expensive treatments for heart failure (HF) may be restricted, clinicians must prioritize their diagnostic approach. While both brain natriuretic peptide and echocardiography play crucial roles in HF diagnosis and prognosis, their availability and affordability might be limited. In such contexts, clinicians should focus on utilizing basic diagnostic tools that offer valuable insights. For instance, ECG emerges as a pivotal tool, offering both screening and prognostic information. Although ECG findings are highly sensitive indicators for HFrEF, they lack specificity, and a normal ECG virtually excludes HFrEF. However, the sensitivity of ECG in HFpEF is lower, with normal findings present in a significant portion of patients. Therefore, in resource-limited settings, clinicians can prioritize utilizing ECG alongside basic diagnostic methods to effectively screen and manage patients with HF, leveraging available resources for optimal patient care (Fig. 1).

Evidence In clinical practice, HF diagnosis commonly relies on symptoms and clinical signs, followed by ECG and NT-proBNP measurements. In case of abnormal tests, a referral for echocardiography should be made to confirm the diagnosis and differentiate between the three main HF types, HFpEF, HFmrEF, and HFrEF, and detect correctable anomalies. These cases are almost invariably of a slow start; acute onset HF is usually diagnosed in the hospital and is occasionally preceded by a period of complaints that are not recognized as HF symptoms [13]. Biomarkers such as soluble ST2 (sST2), galectin-3 (Gal-3), and growth-differentiation factor-15 (GDF-15) are currently emerging as promising indicators of heart failure. Clinical guidelines offer a Class IIb recommendation to contemplate the measurement of sST2 and Gal-3 as supplementary risk factors in heart failure [14]. Telemedicine consultations in HF care provide convenience and time savings, especially for clinically stable patients, making them suitable for outpatient management. In-person assessments are necessary for symptom deterioration, and telemedicine is particularly advantageous in reducing costs, travel expenses, and the need for regular hospital visits, especially in rural areas [15].

In resource-limited India, point-of-care (POC) diagnostic devices offer significant advantages, enhancing healthcare accessibility for a large population. POC enhances diagnostic capacity for severe diseases at a lower cost, making them affordable for many and also offers convenience for continuous monitoring and follow-up tests, reducing turnaround time significantly [16]. This rapid diagnosis is crucial for managing heart failure, especially in remote areas where travel costs are a concern. Recent studies demonstrate the effectiveness of POC testing, such as NT-proBNP testing with the FLEX analyser, in diagnosing and prognosticating congestive heart failure, showcasing the potential of POC devices to improve healthcare outcomes in resource-limited settings [17].

Panel discussion In certain medical conditions, particularly in patients with anemia and infections, general practitioners (GPs) play a crucial role in both diagnosing and managing anemia in individuals suffering from HF. Identifying and addressing anemia becomes a critical aspect of comprehensive patient care. In resource-limited settings, where access to specialized healthcare may be constrained, the initial stages of anemia treatment can be undertaken by skilled nursing professionals. This collaborative approach ensures that timely interventions are implemented, even in environments with limited resources, contributing to better outcomes for patients managing both heart failure and anemia (Table 1).

Evidence The criteria for referral depend on the type of heart failure—HFrEF, HFmrEF, HFpEF, or de novo HF. HF with improved ejection fraction (HFimpEF) is a new classification that is distinctly defined as symptomatic HF with a baseline LVEF ≤ 40%, a ≥ 10-point increase from baseline LVEF, and a second measurement of LVEF > 40% [15]. The choice to refer a patient for a hospital consultation should not impede the prompt commencement or enhancement of prognostic-modifying therapy. Such therapy is valuable for the cardiovascular protection of the patient while awaiting a hospital consultation. An increased rate of referrals to specialty care follow-up may indicate the challenges primary care physicians face in coordinating the growing complexity of modern heart failure (HF) care, such as new pharmacotherapies, catheter-based procedures, and device or surgical therapies [19, 20].

Evidence The use of pharmacological therapy is a cornerstone of HF management. Guidelines are constantly evolving as new evidence emerges. Thus, Tables 2 and 3 represent different guideline recommendations for managing heart failure.

In patients with acute kidney injury during hospitalization for acute HF treatment, MRAs can be started later. Iron therapy should be considered in HF management, especially as improvement is faster when correcting iron levels. According to the American College of Cardiology/American Heart Association/Heart Failure Society of America (ACC/AHA/HFSA), intravenous iron replacement may reasonably enhance functional status and quality of life in patients with New York Heart Association (NYHA) class II and III HF and iron deficiency. Intravenous ferric carboxymaltose (IV FCM) should be considered for treating iron deficiency in symptomatic patients with a left ventricular ejection fraction (LVEF) < 45% to alleviate symptoms, improve exercise capacity, and enhance quality of life (Fig. 2).

Evidence Recent guidelines from the ESC and an expert consensus update by the ACC in 2023 have highlighted the significant benefits of SGLT2i in the treatment of heart failure, regardless of the patient's diabetes status [8, 32]. In particular, the DAPA-HF and EMPEROR trials revealed a significant 30% reduction in heart failure rehospitalization when employing SGLT2i for patients with HFrEF [33]. Moreover, irrespective of diabetes, ARNi has been shown to lower cardiovascular mortality and hospital admissions in individuals with HFrEF. Additionally, ARNi has positively affected left ventricular reverse remodeling, as indicated by decreased N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. MRAs were linked to a lower risk of hospitalization for all causes in older patients with heart failure and concurrent diabetes mellitus or renal insufficiency despite a higher risk of hospitalization for hyperkalemia or acute renal insufficiency. It is worth noting that while MRAs was considered safe for a carefully chosen group of patients with heart failure with concomitant diabetes mellitus or renal insufficiency, the enhanced risk of adverse events was primarily seen in patients with borderline or preserved ejection fraction (Table 4) [34].

Evidence Diabetes is a significant comorbidity in patients with HF, and its presence dramatically increases the risk of cardiovascular morbidity and mortality. Therefore, treating both conditions with optimal therapy as early as possible is essential. The management of concomitant diabetes and HF is complex and still presents therapeutic challenges. To improve patient outcomes, it is crucial to use early and differentiated drug therapy, exhausting all possible treatment options. SGLT2i stands out as the initial class of blood glucose-lowering agents capable of decreasing the incidence of heart failure-related hospitalizations and cardiovascular mortality in diabetic and nondiabetic patients. Therefore, SGLT2i should be used as a first-line therapy for patients with diabetes and HF. Based on data from the DAPA-HF and EMPEROR-Reduced trials, it is anticipated that SGLT2i will be established as a permanent component in the guidelines for treating HF, both in patients with and without diabetes [35] (Fig. 3).

In the SOLOWIST-WHF trial, sotagliflozin yielded comparable results to the placebo in terms of the primary composite outcome (51.0 vs. 76.3%; HR 0.67; 95% CI 0.52–0.85; p < 0.001) which involved patients with T2DM who had recently been hospitalized due to HF [36]. Likewise, in the VERTIS CV trial involving individuals with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease, ertugliflozin exhibited noninferiority to the placebo in terms of MACE [37]. These trials provided evidence of the positive effects of these drugs on heart failure. However, it is essential to note that these benefits did not extend to cardiovascular outcomes, emphasizing that the positive impact on heart failure might not be generalized to all cardiovascular outcomes.

Evidence Initiating SGLT2i therapy in the hospital offers several compelling reasons, with one of the strongest being the prompt and significant clinical benefits that become evident within days to weeks of starting treatment, as reported in studies. For instance, empagliflozin exhibited a remarkable 58% relative decrease in mortality, HF hospitalization, or urgent HF visit 12 days after initiation [38]. The findings of SOLOIST-WHF reinforce these early benefits since initiating sotagliflozin in the hospital or early post-discharge led to early clinical event curve separation [36]. Failure to prescribe SGLT2i to eligible patients at discharge results in a clinically significant increased risk of death and readmission in the first few days to weeks after discharge [38].

Evidence ARB is employed only for patients who cannot tolerate ACEI, making ACEI the cornerstone of treatment for patients with HFrEF for many years. The ACEI and ARB are no longer regarded as the gold standard renin-angiotensin inhibitors for the treatment of HFrEF due to the development of the ARNi sacubitril/valsartan. The landmark PARADIGM-HF trial demonstrated that compared to enalapril, treatment with sacubitril/valsartan was linked to a 20% decrease in cardiovascular death or HF hospitalization; this effect was also seen in individuals with diabetes. As a result, sacubitril/valsartan has been embedded as class I in clinical practice guidelines and is the preferred frontline treatment for HFrEF [39].

Evidence Finerenone, a non-steroidal selective MRAs with more potent anti-inflammatory and antifibrotic effects than steroidal MRAs, has been proven in recent studies to offer more significant benefits in diabetic kidney disease (DKD). Treatment with finerenone was related to a decreased risk of DKD progression, cardiovascular events, myocardial infarction, and hospitalization for HF in the FIDELIO-DKD trial, which included 5734 people with CKD and T2DM [40]. Similarly, in the FIGARO-DKD trial, which involved 7400 individuals with T2D and DKD, finerenone significantly reduced cardiovascular death and nonfatal cardiovascular disease endpoints, including hospitalization for HF. However, finerenone is associated with a risk for hyperkalemia and requires careful serum potassium monitoring when used, like other MRAs [41].

Panel discussion SGLT2i has been demonstrated to reduce the composite renal endpoint in patients by decreasing proximal nephron salt reabsorption, resulting in lower intraglomerular hydrostatic pressures and TGF restoration. Patients with diabetes tend to have a more significant acute decline in the estimated glomerular filtration rate (eGFR) (Table 5).

Evidence Growing evidence from randomized, controlled trials supports the benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiac and renal complications. The indications for SGLT2i have expanded to include glycemic control, reducing atherosclerotic cardiovascular disease (ASCVD), heart failure, diabetic kidney disease, and nondiabetic kidney disease. Although atherosclerosis, cardiac disease, and heart failure are all conditions worsened by kidney disease, there are currently no drugs that specifically protect renal function. However, recent randomized trials, namely DAPA-CKD and EMPA-Kidney, have demonstrated the clinical benefits of dapagliflozin and empagliflozin in improving outcomes for patients with chronic kidney disease. SGLT2i consistently provides cardiorenal protection, reducing the progression of kidney disease and the risk of cardiovascular-related deaths in patients with and without diabetes mellitus [49, 50]. A meta-analysis has shown that SGLT2i alters the risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk but also in patients with chronic kidney disease or heart failure, regardless of diabetes status, primary kidney disease, or kidney function. Another meta-analysis found that irrespective of the estimated glomerular filtration rate (eGFR) levels, SGLT2i significantly lowers the risk of primary renal outcomes in individuals with chronic kidney disease. Consistent benefits have also been observed in patients with type 2 diabetes. However, renal advantages in individuals with ASCVD were mainly identified in those with chronic kidney disease with microalbuminuria, while no discernible benefits were seen in those whose eGFR was less than 60 ml/min/1.73.(57) m² [51]. A meta-analysis of 20 randomized controlled trials involving 63,604 patients with type 2 diabetes, heart failure, or chronic kidney disease found that SGLT2i (dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin) were associated with a significant reduction in the risk of incident atrial fibrillation (AF) compared to the control group. However, there was no significant impact on the risk of stroke. The study suggests that SGLT2i may lower the risk of AF but does not have a substantial effect on the risk of stroke in patients with and without type 2 diabetes [52]. In another meta-analysis of 42 trials involving 61,076 patients with type 2 diabetes indicates that treatment with SGLT2i is associated with a reduced incidence of major adverse cardiovascular events, myocardial infarction, cardiovascular mortality, and all-cause mortality compared to control groups [53].

Evidence The meta-analysis of data from the DELIVER, EMPEROR-Preserved, and three other trials involving a total of 21,947 participants found that SGLT2i significantly reduced the risk of composite cardiovascular death or hospitalization for heart failure, cardiovascular death, hospitalization for heart failure, and all-cause mortality. These benefits were observed consistently in heart failure with mildly reduced or preserved ejection fraction across all five trials. The analysis also revealed that, for the primary endpoint, treatment effects on all categories, including ejection fraction, were relatively consistent. These findings support the use of SGLT2i for all types of HF, regardless of ejection fraction [54].

A recent meta-analysis of the DAPA-HF and EMPEROR-Reduced trials noticed no heterogeneity in CV mortality, even though the EMPEROR-Reduced trial did not significantly reduce CV mortality. Therefore, whether patients with HFrEF have diabetes, dapagliflozin, and empagliflozin are recommended with an ACEI/ARNi, MRAs, and a beta-blocker. Due to their diuretic/natriuretic effects, SGLT2i has additional advantages in reducing congestion and may reduce the need for loop diuretics [36]. According to the meta-analysis of two trials, DAPA-HF and DELIVER, dapagliflozin reduced the risk of death from cardiovascular causes, death from any cause, total hospital admissions for heart failure, and major adverse cardiovascular events (MACEs). The study suggests that dapagliflozin could be an effective treatment for patients with heart failure regardless of ejection fraction [55]. Sotagliflozin has also been demonstrated in hospitalized patients with diabetes and HF and was found to reduce CV death and hospitalization for HF. However, treatment involving SGLT2i might increase the likelihood of recurring genital fungal infections and a minor decline in eGFR upon initiation. However, this reduction is reversible and should not prompt premature discontinuation of the medication [36].

In recent years, research has unveiled novel routes and molecular targets that play crucial roles in the progression of HF. This understanding has led to the development of newer pharmacological drugs that specifically target these sites, offering promising prospects for HF treatment. However, it is important to note that despite their potential benefits, these innovative medications may not be readily available in resource-limited settings due to factors such as cost and infrastructure constraints. Thus, while these advancements hold great promise for improving HF management, their widespread accessibility remains a challenge in certain healthcare environments (Table 6) [57].

There is an unmet requirement for establishing evidence-based therapy for each patient individually with better understanding of pathogenesis of HF. The expertise required in interpreting the results of imaging has to be improved. Hemodynamic sensors/non-invasive strips that can help monitor filling pressure can help de-escalate the dose of diuretics. Controlling risk factors for better clinical outcomes is essential. Even with symptomatic disease, significant barriers to early diagnosis and treatment of HF remain, such as poor awareness of the disease among the general population and suboptimal diagnosis by non-specialist healthcare practitioners, who may have limited access to diagnostic tools such as echocardiography. This is especially concerning in light of the variable clinical presentation of HF and the symptoms (shortness of breath and exercise intolerance) of the conditions with common comorbidities, such as chronic obstructive pulmonary disease, chronic kidney disease (CKD), anemia, and diabetes mellitus. Delays in HF diagnosis are linked to more extended treatment periods, prolonged hospital stays, and death [58].