Practical Guidance on Implementation of Guideline‐Directed Medical Therapy in the Management of Heart Failure: Expert Opinion From the Middle East and Africa Region

Abstract

The 2023 focused update of the European Society of Cardiology 2021 guidelines reviewed the latest scientific evidence and provided recommendations for the guideline‐directed medical therapy for the treatment of heart failure. The class IA level of recommendation for SGLT2i (sodium‐glucose co‐transporter‐2 inhibitor) in heart failure with mildly reduced and preserved left ventricular ejection fraction is of considerable relevance in clinical practice. With a marked increase in the overall burden of heart failure and associated risk factors in the Middle East and Africa region, it is crucial to devise a standardized plan for diagnosis and treatment that accounts for epidemiological nuances, the current evidence on newer treatments, and the health care infrastructure available in the region. A group of 45 cardiologists, moderated by 9 experts from the Middle East and Africa region, reviewed the 2023 focused update of the European Society of Cardiology 2021 guidelines in the context of the current state of guideline‐directed medical therapy‐guided clinical practice. The experts also shared their perspectives on challenges and strategies to overcome for a successful implementation of guideline‐directed medical therapy, particularly SGLT2i, in line with the focused update, for management of heart failure in their respective region/country. Here we present (1) a brief review of the existing literature on the latest burden of disease from the region, (2) a short overview of diagnosis and clinical characteristics of heart failure, (3) a review of the clinical evidence leading to the 2023 update of the European Society of Cardiology 2021 guidelines, and (4) a discussion of the current state and opportunities for implementation of guideline‐directed medical therapy‐guided clinical practice in the region.

Nonstandard Abbreviations and Acronyms

ESC

European Society of Cardiology

GDMT

guideline‐directed medical therapy

HFmrEF

heart failure with mildly reduced EF ejection fraction

HFpEF

heart failure with preserved ejection fraction

HFrEF

heart failure with reduced ejection fraction

MEA

Middle East and Africa

MRA

mineralocorticoid receptor antagonist

MR‐NT‐proANP

midregional N‐terminal proatrial natriuretic peptide

NP

natriuretic peptide

SGLT2i

sodium‐glucose co‐transporter‐2 inhibitor

T2D

type 2 diabetes

Cardiovascular diseases are the major contributors of global disease burden affecting 523 million people. ¹ Cardiovascular disease‐related mortality (20.5 million deaths) accounts for close to a third of all deaths globally, and around 80% of cardiovascular disease deaths occur in low‐ and middle‐income countries. ² Heart failure (HF) is a multifaceted and life‐threatening clinical syndrome characterized by reduced ability of the heart for ventricular filling or ejection of blood due to structural or functional impairment with compensatory neurohormonal activation leading to an insufficient cardiac output. ³ , ⁴ HF remains a major clinical and public health concern affecting 56.2 to 64 million people globally. ⁵ , ⁶

In the Middle East and Africa (MEA) region, increase in the prevalence of HF has been seen between 1990 and 2019. ⁵ This increasing burden of HF might be attributed to factors such as an aging population, high incidence of HF risk factors and comorbidities (coronary artery disease [CAD], type 2 diabetes (T2D), obesity, hypertension, anemia, and chronic kidney disease [CKD]), and urbanization, as well as the poor health systems in many Sub‐Saharan Africa countries to manage the burden. ⁴ , ⁷ Although CAD (~70%) constitutes a major reason of HF in the Western countries, it is CAD (~55%) followed by dilated nonischemic cardiomyopathy (16%–18%) and hypertension (10%–12%) in the Middle East. ⁸ Literature reported that Middle East countries present lower incidence of CAD and atrial fibrillation (AF), which could be better explained by the younger age of the population, limited use of continuous ECG monitoring, and underrepresentation of HF with preserved ejection fraction (HFpEF) compared with Western countries. ⁸ In the Sub‐Saharan Africa region, hypertensive heart disease and dilated cardiomyopathy are the prevalent risk factors for HF compared with CAD. Also, HIV‐related cardiomyopathy has been identified as the most common clinical cardiac complications associated with HIV in Sub‐Saharan Africa, leading to HF. ⁹ Additionally, high incidence of comorbidities, underuse of the ambulance services, poor traffic infrastructure and the heavy traffic burden, poor health system leading to weak prevention strategies, undiagnosed risk factors, and low detection and treatment rates might attribute to the increased HF‐related mortality and morbidity in this region. ⁸ Therefore, it is crucial to shift the focus to prevention and early detection of HF and devise a standardized plan for diagnosis and treatment that takes into consideration the epidemiological nuances, the current evidence on newer treatments, and the health care infrastructure available in the region. Moreover, the structural and health‐system related hurdles could be dealt with by the development of regional‐specific guidelines, improving awareness, exploring digital technology, and increasing funding and reimbursements. ⁴

A scientific discussion meeting comprising 45 experts in the field of HF from the MEA region came together to discuss recent updates on the 2021 European Society of Cardiology (ESC) guidelines and shared their perspective on the current state, challenges, and ways for successful implementation of guideline‐directed medical therapy (GDMT) in the management of HF. Here we present an overview of the diagnosis and clinical characteristics of HF and review of the clinical evidence leading to the 2023 update of the 2021 ECS guidelines and summarize the insights gathered during the meeting.

DIAGNOSIS OF HF

HF is a clinical syndrome accompanied by cardinal symptoms (dyspnea, orthopnea, reduced exercise tolerance, lethargy, fatigue, nocturnal cough, wheeze, ankle swelling, anorexia) and signs (cachexia, tachycardia, hepatojugular reflux, elevated jugular venous pressure, displaced apex beat, right ventricular heave, third heart sound, edema, ascites) that are secondary to functional and/or structural abnormality of the heart (Figure 1). ¹⁰ , ¹¹ , ¹² , ¹³

Figure 1. Symptoms and signs of HF.

*These are specific for heart failure with reduced ejection fraction. HF indicates heart failure.

The diagnosis of HF is performed through a series of investigations including identification of clinical symptoms and signs through medical history, physical examinations, routine blood tests, and through specific findings on imaging and biomarker tests (Figure 2). Echocardiography and measuring of natriuretic peptide (NP) in plasma have become cornerstones for the confirmatory diagnosis of HF. ¹¹ However, there are considerable variations in the ways both these modalities are implemented in clinical practice. Although quality standards for reporting of echocardiography have been detailed by professional societies, ¹⁴ considerable intra‐ and interobserver variability is a known limitation of echocardiography. Nevertheless, echocardiography is the key diagnostic tool for the assessment of left ventricular ejection fraction (LVEF) and other functional and structural abnormalities. Measurement of NP levels in plasma is a minimally invasive method of laboratory evaluation to rule out HF recommended by both the American Heart Association and ESC. ¹¹ , ¹⁵ , ¹⁶ , ¹⁷ Among the 3 plasma NPs, BNP (B‐type natriuretic peptide), NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), and MR‐NT‐proANP (midregional N‐terminal proatrial natriuretic peptide), strong evidence exists for the use of BNP and NT‐proBNP levels for ruling‐in of HF diagnosis (especially for HFpEF) as well as to assess its severity and prognosis. ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ Furthermore, the diagnostic value of NT‐proBNP is higher than BNP due to its stability and longer half‐life. ¹⁸ , ¹⁹ The ESC recommends a single cut point of 300 pg/mL NT‐proBNP, irrespective of the patient’s age, as well as age‐adjusted cutoffs to rule in HF in the emergency department. ¹⁶ , ²⁰ Use of NT‐proBNP for ruling out HF resulted in considerable reductions in initial hospitalization and subsequent inpatient care among patients visiting the emergency department with signs and symptoms of HF, ²² , ²³ , ²⁴ resulting in lower health care resource use and total treatment costs. ²⁵ , ²⁶ Although measuring NP levels is considered a critical tool for early diagnosis of HF, its implementation in clinical settings differs depending on variations in local health care systems, as reported in the ESC‐Heart Failure Association Atlas Survey. ²⁷ Moreover, it is important to consider the confounding factors like age, sex, and comorbidities while interpreting NP levels. In addition, race‐based differences in NT‐proBNP concentrations can result in large differences in absolute risk estimation of HF. ²⁸ Hence, applying a single cut point that was based on data from the Western population to screen patients of a geographically diverse set can therefore lead to misclassification of risk.

Figure 2. Diagnostic algorithm for HF.

AF indicates atrial fibrillation; BNP, B‐type natriuretic peptide; CAD, coronary artery disease; CHD, coronary heart disease; CMP, cardiac myopathy; CMR, cardiac magnetic resonance; CTCA, computed tomography coronary angiography; HbA1c, glycated hemoglobin; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LA, left atrium; LV, left ventricular; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PCWP, pulmonary capillary wedge pressure; SPECT, single‐photon emission computed tomography; SR, sinus rhythm; and TSAT, transferrin saturation. ^aBlood investigations need to differentiate HF from other conditions. Chest x‐ray examines the supportive evidence of HF. ^bOnly commonly used indices are listed in the Table. For less commonly used indices, refer to the consensus document of the European Society of Cardiology/Heart Failure Association.

Moreover, lack of standardized definition of HF across various clinical registries can significantly impair timely HF prevention and management. ²⁹ Considering the vast geographical variation within the MEA, this gap can result in poor HF control.

There are many distinct classifications of HF based on location: left ventricular, right ventricular, or biventricular; time of onset; acute or chronic; LVEF: HF with reduced ejection fraction (EF) (HFrEF; EF ≤40%), HF with mildly reduced EF (HFmrEF; EF 41%–49%), and HFpEF (EF ≥50%). ¹¹ , ³⁰ A new term, HF with improved EF, was recently introduced and defined as patients with HF with baseline EF ≤40% with a ≥10 point EF increase and a second measurement of EF >40%. ³ , ³¹ The diagnosis of HFrEF is mostly established by echocardiography with LVEF ≤40% in the presence of symptoms and signs of HF. Cardiac magnetic resonance, or rarely nuclear techniques, can be used if EF is not appropriately measured by echocardiography. ¹¹ The diagnosis of HFmrEF is confirmed by echocardiography in the presence of symptoms and/or signs with LVEF of 41% to 49%. Additional confirmatory diagnosis for HFmrEF includes elevated NPs and presence of structural heart disease (left atrial enlargement, left ventricular hypertrophy). ¹¹ The diagnosis of HFpEF remains a challenge for the physician due to (1) overlapping symptoms and signs of HFpEF with normal aging, (2) no clear consensus of the definition of HFpEF, and (3) NP testing and resting echocardiography are not used in many patients subject to limitations in the diagnosis of HFpEF. ¹² Although 2 score‐based algorithms (H₂FPEF [Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age >60, elevated Filling pressures] and HFA‐PEFF [Heart Failure Association Pre‐test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology]) were developed recently and used in various studies, both provided inconsistent results. ¹¹ According to the ESC, the simplified diagnostic criteria for HFpEF includes symptoms and signs of HF with an LVEF ≥50% and sign of functional and/or structural cardiac abnormalities in line with the occurrence of left ventricular (LV) diastolic dysfunction/elevated LV filling pressures, including higher NPs. ¹¹ In cases of diagnostic ambiguity, additional tests, such as cardiopulmonary exercise testing, exercise stress testing, and invasive hemodynamic testing, can be conducted. Moreover, invasive hemodynamic exercise testing is the confirmatory test for HFpEF, and elevation of several objective noninvasive markers of raised LV filling pressures (LV mass and LV volume index, ratio of early mitral inflow velocity (E) and early mitral anular tissue doppler velocity (e) (E/e)’ ratio, NPs, pulmonary artery systolic pressure) increases the probability of HFpEF. Additionally, a diastolic echocardiographic stress test should be performed if resting echocardiographic and laboratory markers are equivocal. ¹¹ All of these factors should be taken into consideration while confirming a diagnosis of HFpEF. The details of special investigations to help diagnose HF in patients with varied clinical presentations and/or presence of comorbidities with HF are presented in Figure 3.

Figure 3. Diagnosis of heart failure based on cause and/or comorbidities.

5‐HIAA indicates 5‐hydroxyindoleacetic acid; ACE, angiotensin‐converting enzyme; ANA, anti‐nuclear antibody; ANCA, anti‐nuclear cytoplasmic antibody; BP, blood pressure; CAD, coronary artery disease; CK, creatinine kinase; CMP, cardiomyopathy; CMR, cardiac magnetic resonance; CT, computed tomography; ECHO, echocardiography; EMB, endomyocardial biopsy; FDG, fluorodeoxyglucose; GGT, gamma‐glutamyl transferase; LFT, liver function test; PET, positron emission tomography; and TFT, thyroid function test.

However, lack of data in MEA limits the accurate estimation and comparison of prevalence of these categories, whereas the epidemiology of HF is well‐understood in Western countries. Although recent data from registries have provided insights on the prevalence of HFpEF in MEA, the estimates vary significantly (10%–25% in the Middle East and 22%–75% in North Africa). ⁷ In Sub‐Saharan Africa, the prevalence of HFmrEF and HFpEF is still lower than in Western countries. Data from the THESUS (The Sub‐Saharan Africa Survey on Heart Failure) registry report the prevalence at 19.6% for HFmrEF and 27.3% for HFpEF. ³²

GDMT IN THE MEA REGION

In recent years, the landscape of HF management has experienced a major revolution with the introduction of GDMT, which includes a combination of 4 main drug classes: renin‐angiotensin system inhibitors, evidence‐based β‐blockers, mineralocorticoid inhibitors, and SGLT2i (sodium‐glucose co‐transporter‐2 inhibitor) in the treatment and management of HF. Use of GDMT has demonstrated considerable benefits in terms of reduction in cardiovascular and all‐cause mortality and HF hospitalizations in patients with HFrEF. ³³ , ³⁴ Although GDMT provided clear benefits in patients with HFrEF, GDMT is not optimally used in the clinical setting, and globally there is a considerable gap in terms of insufficient awareness about the initiation and titration of GDMT‐guided medications, especially in the presence of comorbid conditions. ³³ , ³⁴ , ³⁵ , ³⁶ The scenario is similar in the MEA region. A real‐world study including 171 patients with HF from Oman reported that although 67 patients were prescribed GDMT, the dose optimization was not adequate and the frequent reasons behind GDMT noncompliance were presence of renal impairment, hypotension, and hyperkalemia. ³⁷ Additionally, patients prescribed with triple GDMT (renin‐angiotensin system inhibitors, β‐blockers, mineralocorticoid inhibitors) were associated with significantly lower emergency room visits (P=0.03), length of hospital stay (P=0.012), hospital admissions (P=0.005), and overall major adverse events (P=0.005). ³⁷ Similarly, a real‐world study from Palestine (N=605) revealed only one‐third (38.7%) of patients were prescribed triple GDMT, and age, CKD, T2D, and HF‐related hospitalizations were the frequent causes of underuse of GDMT. ³⁸ A regional Arab Middle East (Gulf Region) experience, including 2427 patients with HF, found similar observations on GDMT use and reported that patients managed by HF specialists frequently received recommended target doses of GDMT than those treated by general cardiologists. ³⁹ Thus, a major gap between clinical practice and guideline recommendations for appropriate use of GDMT exists, which may negatively impact patients’ quality of life, symptoms, and survival. ³⁹ However, considering the small sample sizes from the Oman and Palestine studies, there is inadequate representation of broader patients with HF in this region, limiting the generalizability of findings.

2023 FOCUSED UPDATE ON GDMT FOR HF

The 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF summarized the recent evidence that further strengthens the panel’s recommendations on the use of GDMT in the management of HF, particularly those with HFmrEF and HFpEF. ¹³ The key studies that led to the 2023 update of the ESC 2021 guideline are listed in Table S1. The current update was focused on new evidence supporting the use of SGLT2i in the HFmrEF and HFpEF phenotypes, intensified therapy for the management of acute HF, and finerenone, a new selective nonsteroidal mineralocorticoid receptor antagonist (MRA) for the prevention of HF in patients with T2D and CKD (Table). ⁴⁰ SGLT2i, dapagliflozin, or empagliflozin, in addition to the triad therapy of an angiotensin‐converting enzyme inhibitor/angiotensin receptor neprilysin inhibitor, a β‐blocker, and an MRA for the treatment of HErEF was part of the ESC 2021 update. ¹¹

Table 1.

New Recommendations in the 2023 Update of the European Society of Cardiology 2021 Guidelines for the Management of HF

Recommendations	Class	Level
AHF
Intensive strategy: Initiation and rapid up‐titration of GDMT‐directed triple therapy and/or SGLT2i and frequent postdischarge visits in the first 6 weeks to reduce risk of HF rehospitalization or death (STRONG‐HF)	I*	B§
Symptomatic HFrEF, with iron deficiency
IV iron supplement is recommended to alleviate HF symptoms and improve quality of life (PIVOTAL)	I*	A‡
IV ferric carboxymaltose or ferric derisomaltose should be considered to reduce the risk of HF hospitalization (IRONMAN, AFFIRM‐AHF)	IIa†	A‡
Symptomatic HFmrEF
SGLT2i (dapagliflozin or empagliflozin) is recommended to reduce the risk of HF hospitalization or cardiovascular death (EMPEROR‐Preserved, DELIVER)	I*	A‡
In patients with iron deficiency: IV iron supplement is recommended to alleviate HF symptoms and improve quality of life (PIVOTAL) IV ferric carboxymaltose or ferric derisomaltose should be considered to reduce the risk of HF hospitalization (IRONMAN, AFFIRM‐AHF)	I*	A‡
	IIa†	A‡
Symptomatic HFpEF
SGLT2i (dapagliflozin or empagliflozin) is recommended to reduce the risk of HF hospitalization or cardiovascular death (EMPEROR‐Preserved, DELIVER)	I*	A‡
Prevention of HF in patients with T2DM and CVD
SGLT2i is recommended to reduce the risk of HF hospitalization or cardiovascular death (DAPA‐CKD, EMPA‐KIDNEY, FIDELIO‐DKD, FIGARO‐DKD)	I*	A‡
Finerenone is recommended to reduce the risk of HF hospitalization (FIDELITY pooled analysis, FIDELIO‐DKD, FIGARO‐DKD)	I*	A‡

AFFIRM‐AHF indicates Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency; AHF, acute heart failure; CVD, cardiovascular disease; DAPA‐CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; EMPA‐KIDNEY, Empagliflozin Once Daily to Assess Cardio‐Renal Outcomes in Patients With Chronic Kidney Disease; EMPEROR‐Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure with Preserved Ejection Fraction; FIDELIO‐DKD, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease; FIDELITY, FIDELIO‐DKD and FIGARO‐DKD Trial Programme Analysis; FIGARO‐DKD, Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease; GDMT, guideline‐directed medical treatment; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRmrEF, heart failure with mildly reduced ejection fraction; IRONMAN, Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency; PIVOTAL, Proactive IV Iron Therapyin Haemodialysis Patients; SGLT2i, sodium‐glucose co‐transporter‐2 inhibitor; STRONG‐HF, Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT‐proBNP Testing, of Heart Failure Therapies; and T2D, type 2 diabetes.

^*Class I: Recommended.

^†Class IIa: Should be considered.

^‡Level of evidence A: Data derived from multiple randomized clinical trials or meta‐analyses.

^§Level of evidence B: Data derived from a single randomized clinical trial or large non‐randomized studies.

Management of Patients With Symptomatic HFmrEF and HFpEF

The 2023 update recommended use of SGLT2i in patients with HFmrEF and HFpEF. The recommendation is based on findings of the EMPEROR‐Preserved (empagliflozin; Empagliflozin Outcome Trial in Patients With Chronic Heart Failure with Preserved Ejection) ⁴¹ and DELIVER (dapagliflozin; Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) ⁴² studies and a meta‐analysis, ⁴³ which included patients with chronic HF with LVEF >40% covering both the mildly reduced and preserved phenotypes. Both clinical studies and the meta‐analysis provided the basis for class IA recommendation for use of SGLT2i to reduce the risk of HF hospitalizations and cardiovascular mortality among patients with current or previous symptomatic HFmrEF and in patients with HFpEF. ¹³

Empagliflozin and dapagliflozin effects were mainly driven by a reduction in HF hospitalizations, and there was no significant reduction seen in cardiovascular deaths. However, the panel’s decision was based on the primary end point (ie, the composite of HF hospitalization or cardiovascular death) of the 2 studies. ⁴¹ , ⁴² The EMPEROR‐Preserved trial reported on the effects of empagliflozin 10 mg once daily or placebo in 5988 patients with HF with LVEF >40%. At a median follow‐up of 26.2 months, empagliflozin reduced cardiovascular death or hospitalization for HF (hazard ratio [HR], 0.79; P<0.001); the effects were seen in patients with and without T2D. ⁴¹ The DELIVER trial reported on the effects of dapagliflozin 10 mg once daily compared with placebo in 6263 patients with HF with LVEF >40%. Dapagliflozin significantly reduced cardiovascular death or worsening HF (HF hospitalization or urgent HF visit; HR, 0.82; P<0.001), and these cardiovascular effects were independent of patient’s T2D status. ⁴² Although this study included patients with comorbid conditions and those on concomitant medications that closely resemble the real‐world setting, the proportion of Black patients was considerably lower than others. Thus, the study findings should be put in the context of the African population, especially on high blood pressure. In this regard, a pooled analysis of the data set from the 2 EMPEROR trials assessed the safety and efficacy of empagliflozin according to Black versus White patients. The pooled results showed higher risk of HF in Black patients than in White patients. However, when assessed irrespective of ejection fraction, the efficacy and safety of empagliflozin was similar in Black and White patients with HF, thereby suggesting a potential enhanced efficacy in Black versus White patients, particularly with HFrEF. Considering that Black patients may be predisposed to greater fluid retention, they may derive more benefit from empagliflozin’s decongestive properties. ⁴⁴

In the prespecified EMPEROR‐Preserved and DELIVER meta‐analysis, a 20% reduction in the composite end point of cardiovascular death or first hospitalization for HF (HR, 0.80; P<0.001) was further confirmed, along with a significant reduction of 26% (HR, 0.74; P<0.001) in HF hospitalization. ⁴³ Additionally, a pooled analysis of the DAPA‐HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER trials demonstrated a significant reduction in cardiovascular death (HR, 0.86 [95% CI, 0.76–0.98]; P=0.027) and all‐cause mortality, further reinforcing the mortality benefit of SGLT2i across the HF spectrum. ⁴⁵ A pooled analysis of the DAPA‐HF study in patients with HFrEF and DELIVER and prespecified analysis of the DELIVER study showed that dapagliflozin significantly reduced the risk of all‐cause and HF hospitalizations, and that the effect of dapagliflozin did not differ by ejection fraction. ⁴⁵ , ⁴⁶

Based on the collective evidence to date, the ESC recommendation for the management of chronic HF is summarized in Figure 4.

Figure 4. Management of HF.

ACE‐I indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CV, cardiovascular; GDMT, guideline‐directed medical treatment; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; and SGLT2i, sodium‐glucose co‐transporter‐2 inhibitor.

Role of SGLT2i in Management of Patients With Acute HF

In terms of treatment for management of acute HF, there is no new recommendation from the last 2021 ECS guidelines. ¹¹ The 2023 update recommends high‐intensity care during the predischarge and early postdischarge phases for reduction in HF readmissions or all‐cause deaths among patients hospitalized for an episode of acute HF. This recommendation was based on the STRONG‐HF (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT‐proBNP Testing, ofHeart Failure Therapies) trial, which showed that high‐intensity care starting early (reaching half of the target doses within 2 days before anticipated discharge) and rapid up‐titration (full target doses within 2 weeks of discharge) of GDMT‐directed quadruple drug (angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker or angiotensin receptor neprilysin inhibitor, with a β‐blocker and an MRA) and close follow‐up in the first 6‐weeks resulted in 34% reduction in the risk of HF readmission or all‐cause death at 180 days (adjusted relative risk, 0.66; P=0.0021) versus usual care in patients with acute HF hospitalization. ⁴⁷ The safety profile was similar between the 2 management strategies. ⁴⁷ Although the STRONG‐HF trial did not use SGLT2i, the findings corroborate the beneficial effects of GDMT‐directed oral HF medications, and further substantiate the importance of implementing target doses of these medications to achieve maximal benefit. The EMPULSE (Empagliflozin in Patients Hospitalized with Acute Heart Failure Who Have Been Stabilized) trial tested the efficacy of the early initiation of SGLT2i empagliflozin in patients hospitalized for acute HF. The clinical benefit (death from any cause, number of HF events, and time to first HF event, or a ≥5 point difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire‐Clinical Summary Scores total symptom score at 90 days, assessed using the win‐ratio method) was achieved in more patients treated with empagliflozin compared with placebo (stratified win ratio, 1.36 [95% CI, 1.09–1.68]; P=0.0054) independent of LVEF and diabetes status. ⁴⁸ This study further adds on to the collective evidence of the beneficial effects of SGLT2i in reducing HF hospitalizations and cardiovascular death across the full clinical spectrum of HF.

Role of SGLT2i in Managing Risk of HF in Patients With Comorbidities

There is a wealth of evidence suggesting beneficial effects of SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin) on cardiovascular outcomes in patients with T2D. ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ Use of SGLT2i has resulted in significant reductions in risk of HF hospitalizations, major cardiovascular events, end‐stage renal dysfunction, along with an improved range of renal outcomes, and cardiovascular death in patients with T2D. The recent update focuses on therapeutic strategies to prevent HF in patients with CKD and T2D.

Two large clinical studies DAPA‐CKD (Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease)and EMPA‐KIDNEY provided evidence for the efficacy of SGLT2i in reducing HF hospitalizations and cardiovascular deaths in patients with CKD. ⁵⁴ , ⁵⁵ In the DAPA‐CKD study, dapagliflozin 10 mg significantly reduced the risk of HF hospitalization or cardiovascular death by 29%. ⁵⁴ In the EMPA‐KIDNEY (Empagliflozin Once Daily to Assess Cardio‐Renaloutcomes in Patients With Chronic Kidney Disease) study, empagliflozin 10 mg significantly reduced the composite primary end point of progression in kidney disease or cardiovascular death by 28%. ⁵⁵ In a meta‐analysis of SGLT2i studies in CKD and HF clinical studies, a 23% reduction in patients with T2D and 21% in patients without T2D in HF hospitalizations and cardiovascular deaths was observed. Taking into consideration the cumulative evidence, SGLT2i is recommended for prevention of HF hospitalization and cardiovascular death in patients with CKD and T2D with an estimated glomerular filtration rate >20 to 25 mL/min per 1.73 m².

In patients with diabetic kidney disease, a new treatment, finerenone, is recommended for the prevention of HF hospitalization. Finerenone, a selective, nonsteroidal MRA, significantly reduced the risk of the composite cardiovascular outcome, including HF hospitalization in patients with CKD and T2D with a urinary albumin‐to‐creatinine ratio 30 to 300 mg/g and an estimated glomerular filtration rate >25 mL/min per 1.73 m². ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹

LIFESTYLE MODIFICATION FOR PATIENTS WITH HF

Successful treatment of HF requires careful attention to lifestyle and self‐care in addition to adhering to the medications. ⁶⁰ , ⁶¹ Maintaining a healthy body weight and limiting salt (sodium) and fluids helps avoid fluid buildup and alleviates HF symptoms. Limiting consumption of alcohol and quitting smoking can alleviate the risk factors for adverse cardiovascular outcomes. In patients with HFrEF, cardiac rehabilitation is often advised, which includes mild to moderate exercise under the guidance of a medical team to improve exercise tolerance. An active lifestyle, which incorporates brisk exercise, is recommended for all patients with HF to improve exercise capacity, quality of life, and reduce HF hospitalization (Figure 4). ⁶² Last, patients and their family members often value shared decision‐making and health education. A health care practitioner–patient–caregiver collaborative relationship is essential to effectively address and optimize adherence to medical recommendations.

Outcome in HF is worsened by presence of comorbidities, and these will require appropriate management to improve outcomes in HF. These comorbidities could be cardiac (eg, AF, hypertension, chronic coronary syndrome, and valvular heart disease) or noncardiac comorbidities (eg, diabetes, CKD, iron deficiency, obesity, sarcopenia/frailty, sleep disordered breathing, electrolyte abnormalities, thyroid dysfunction, and depression). ¹¹

AF and HF commonly coexist, potentiating the occurrence of each other with worse outcomes. ⁶³ , ⁶⁴ The interwoven relationship is related to structural cardiac remodeling, activation of neurohormonal systems, rate‐related LV dysfunction, and common risk factors. ⁶³ , ⁶⁵ The burden of AF in heart failure increases with age and HF severity. The presence of AF in HF increases both stroke risk and mortality. ⁶⁶ , ⁶⁷ Management of patients with coexistent AF and HF will include elimination of the risks and triggers, management of HF, prevention of embolic events, rate control, or rhythm control. ⁴⁰ SGLT2i use in the treatment of HF with all its extended kidney and metabolic benefits helps in the amelioration of some of the noncardiac comorbidities. The use of supplemental intravenous iron (ferric caboxymaltose) is now guideline recommended for the management of iron deficiency in patients with HFrEf and HFmrEf to reduce symptoms and improve quality of life. ⁴⁰ The full discussion of the varied cardiac and noncardiac comorbidities is beyond the scope of this document.

STATUS OF GDMT IN THE MEA REGION

A clear dichotomy is seen in terms of the status of GDMT implementation in MEA countries for the management of HF (Figure 5). Although the key challenge in applying GDMT in the African countries are poor accessibility and affordability of GDMT drugs and health care infrastructure; for the Middle East countries, it is to overcome the therapeutic inertia and to drive optimum initiation and strengthening of GDMT drugs in routine practice.

Figure 5. Status of GDMT in the MEA region.

AI indicates artifical intelligence; ECHO, echocardiography; HF, heart failure; HFA, Heart Failure Association; HFpEF, heart failure with preserved ejection fraction; H₂FPEF, Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age >60, elevated Filling pressures; GDMT, guideline‐directed medical treatment; MEA, Middle East and Africa; NHS, National Health Scheme; and PEFF, Pre‐Test Assessment, Echocardiography & Natriuretic Peptide, Functional Testing, Final Etiology.

The experts from the African countries highlighted lack of comprehensive local HF guidelines and National Health Scheme as major obstacles in implementing GDMT for HF management. Although cardiologists are aware of the international HF guidelines, there is a lack of awareness of GDMT among primary care physicians as well as availability of key diagnostic modalities, such as echocardiography and biomarker testing at the primary care centers. The lack of local HF guidelines and prevalence of comorbidities such as hypertension and ischemic and rheumatic heart disease in African populations adds to diagnostic delays at the point‐of‐contact/primary care centers and timely initiation of GDMT drugs. The National Health Scheme does not include all 4 GDMT drugs in most of the African countries, and newer preventive therapies such as SGLT2i are not included in the national HF guidelines. Thus, GDMT cost will be an out‐of‐pocket expense for the majority of the patients, making long‐term compliance a challenge. The health care systems in African countries are highly heterogenous, and vast disparity exists between the primary and secondary care centers in terms of medical expertise and infrastructure. At the point of contact, a general practitioner or nurse at a community health care center having access to tools (ECG, ultrasound, x‐ray, NT‐proBNP testing) for the identification of HF is critical for accurate and timely diagnosis of HF. However, fragmented health care systems and different practice settings within a country challenge uniform implementation of GDMT. Moreover, health care policy makers in the African countries focus more on highly prevalent infectious disease as compared with noncommunicable diseases. There is an urgent need for policy makers and health care professionals to collaborate and develop national HF guidelines and update the National Health Scheme to curb the increasing burden of HF in the region.

On the other hand, in the Middle East countries, availability and accessibility are optimal, and good implementation of GMDT is seen across health care system. The national HF guidelines are aligned and up to date as per the international treatment guidelines and recommendations, and all GDMT‐recommended drugs, including SGLT2i, are incorporated in the national guidelines. The 2023 focused update from the Saudi Arabia guidelines supplemented the pharmacological treatment of HF with recommendations on newer therapies, such as SGLT2i. ⁶⁸ Despite the overall high awareness and accessibility, compliance to GDMT is low in the MEA region. In Iran, 60.3% to 71.4% of patients reported poor self‐reported HF medication adherence, ⁶⁹ , ⁷⁰ , ⁷¹ whereas 53.6% of patients in Saudi Arabia ⁷² and 47.1% of patients in Yemen were reported to have low adherence to their HF medications. ⁷³ There is also therapeutic inertia among clinicians, and patient acceptance of multiple drugs is low, resulting in underuse of GDMT medications. Clinicians find sequencing of GDMT drugs challenging, and high prevalence of obesity, diabetes, and hyperlipidemia among patients with HF further complicates the overall pharmacotherapeutic management of these patients.

The experts from the MEA region agreed on certain strategies that could boost GDMT implementation in the region. Development and dissemination of education programs for health care professionals directed toward awareness of signs and symptoms of HF, diagnostic modalities, and implementation of GDMT is of paramount importance to elevate the status of HF management in the MEA region. Focus should be on educating health care professionals at the primary level for early detection and referral of patients to specialist care. Efforts should be made to train nurses and involve them in HF care. Additionally, educating patients on disease awareness, benefits, and side effects of GDMT drugs is crucial to ensuring long‐term treatment adherence. Experts also suggested using artificial intelligence to integrate imaging and biomarker testing and assist in early diagnosis of HF, especially HFpEF.

Although several registries from the Middle East countries, such as HEARTS‐Chronic (Heart Function Assessment Registry Trial) , PEACE MENA (The Program for the Evaluation and Management of Cardiac Events in the Middle East and North Africa), Gulf CARE (Gulf Acute Heart Failure Registry), Egyptian cohort of the European Society of Cardiology Heart Failure Long‐Term registry, and Oman Acute Heart Failure Registry have been initiated, few have been done in Africa, THESUS, and the African cohort of the INTER‐CHF (International Congestive Heart Failure), ⁷⁴ , ⁷⁵ whereas THESUS II (The Sub‐Saharan Africa Survey of Heart Failure) is currently recruiting. Generation of local data is key for effectively engaging policy makers to recognize the need to allocate resources toward HF management. Thus, establishing real‐world databases and registries at national or regional levels to evaluate precise burden of disease and risk factors among the African population is the need of the hour. Data gathered from these registries can support future directions in the MEA region for betterment of the overall management of HF, such as focused engagement with the governments and policy makers in updating national HF guidelines, setting up of HF clinics, and overcoming barriers to accessibility and affordability of GDMT drugs. Although real‐world settings can provide insights into clinical practice, results from these studies are subjected to several confounding factors that include patient selection and bias, differences in patient baseline characters, and follow‐ups. In this regard, real‐world evidence complements findings from randomized controlled trials but cannot fully replace a well‐controlled and a rigorously designed randomized controlled trial. Additionally, lack of long‐term follow‐up data limits the understanding of efficacy and safety of GDMTs.

Developing institutional protocols can help streamline efforts toward optimal use of available health care resources. The Heart Failure Working Group of the French Society of Cardiology has suggested a practical intravenous diuretic administration protocol to provide ambulatory care for worsening HF. ⁷⁶ Studies also support that remote management of HF can reduce HF hospitalizations. ⁷⁷ Development of a practice algorithm in concordance with the international guidelines that takes into consideration the available resources and addresses local needs may be more impactful for both the clinicians and patients. ⁶⁸ , ⁷⁸ , ⁷⁹

PRACTICAL GUIDANCE OF IMPLEMENTING GDMT WITH FOCUS ON UPTAKE OF SGLT2i

The experts from the MEA region unanimously agreed on the usefulness of SGLT2i clinical studies in patients with HF and CKD in terms of phenotyping patients with HF. The use of 1 dose of an SGLT2i across the entire HF spectrum is a positive attribute for clinical practice, especially for patients with HFpEF, who are often difficult to diagnose due to heterogeneity and complex algorithms that are challenging, especially in resource‐poor settings. ⁸⁰ Additionally, the cardiovascular benefits of SGLT2i are seen irrespective of comorbidities like diabetes and CKD with an estimated glomerular filtration rate >25 mL/min per 1.73 m². A multidisciplinary approach is imperative for ensuring optimal implementation of GDMT. ⁸¹ Collaborative efforts of cardiologists, primary care physicians, diabetologists, nephrologists, and nurses are needed for the treatment of HF and overall management of potential side effects. However, it is challenging to implement a multimodal team in practice even in developed countries such as the United States, as seen in the CHAMP‐HF (Change the Management of Patients With HF) registry, which included 3518 outpatients with chronic HFrEF receiving at least 1 oral medication for management of HF. The study showed significant gaps in the real‐world use of GDMT for HF. ³⁵ An integrated engagement between cardiologists and primary care physicians, diabetologists, and nephrologists can help understand the good experience with SGLT2i in their respective practices, for successful implementation of GDMT, and particularly SGLT2i, in the management of HF. SGLT2i is approved for the management of T2D and has demonstrated positive outcomes for cardiovascular outcomes trials and various HFrEF, HFpEF, CKD, and hospitalized HF trials. Primary care physicians have experience using β‐blockers and angiotensin‐converting enzyme inhibitors for the management of hypertension. Diabetologists are aware of the use of SGLT2i as a glucose‐lowering agent, and their experience can be useful to cardiologists when initiating SGLT2i. Diabetologists should also ensure a thorough cardio workup such as echocardiography, and NT‐proBNP tests have been performed on a regular basis to monitor cardiac function of patients with HF with diabetes. In patients with HF and type 1 diabetes or pancreatic insufficiency, SGLT2i is contraindicated, and cardiologists should work with diabetologists for optimal disease management. Diabetic ketoacidosis can occur with SGLT2i in hospitalized patients with HF with diabetes, and vigilance is needed in patients with diabetes who are fasting and who are extremely unwell or have sepsis. The effects of loop diuretics and the favorable effect of SGLT2i on renal physiology are required for their beneficial effects in HF. Communication with nephrologists is crucial for optimal dosing of loop diuretics when initiating SGLT2i. Nurses and pharmacists are integral members of the multidisciplinary team providing specialized HF care and patient support.

Approaches for treatment sequencing in patients with HF will vary with the phenotype, presence of comorbidities, and practice setting. The conventional sequencing of therapies in HFrEF comprising gradual up‐titration of GDMT drugs has several disadvantages to patients and is inefficient for health care workers. The optimal therapeutic benefit is delayed by ≈6 months, and patients do not receive benefits of early treatment initiations, such as reduction in mortality and HF hospitalizations. Significant reductions in 90‐day all‐cause mortality and HF readmissions was seen with early initiation of SGLT2i. ⁸² Simultaneous or rapid sequence initiation of quadruple medical therapy for HF with an angiotensin receptor neprilysin inhibitor, β‐blocker, MRA, and SGLT2i may have significant benefit by reducing the risk of death by 73% over 2 years. ⁸³ Patients benefit with rapid initiation of HFrEF drugs because they reduce mortality and hospitalizations, improve quality of life, may avoid the need for implantable cardioverter‐defibrillator and transplant/ventricular assist devices, and reduce visits to the hospital. However, treatment sequencing should be well planned considering individual patient profile and safety monitoring requirements. ¹¹

Last, patients are in the center of the multidisciplinary team, and effective physician–patient communication are key to shared decision‐making. Patients should be made aware of the potential benefits of all GDMT drugs and their therapeutic as well as preventive effects on overall management of HF. An SGLT2i is associated with increased risk of genital tract infections, ⁴³ , ⁴⁸ , ⁸⁴ , ⁸⁵ and patients should be informed about the importance of hydration and practicing appropriate hygiene measures to lower the chances of mycotic infections. This will ensure improved treatment adherence for optimal benefits from GDMT medications in patients with HF.

Providing a multidisciplinary HF team to care for patients hospitalized with HF was associated with better adherence to GDMT postdischarge in MEA. ⁸⁶ In addition to the aforementioned strategies, addressing clinician’s inertia in prescribing GDMT, improving its affordability, and electronic health record‐integrated interventions can further optimize GDMT use in those with HF. ⁸⁷

CONCLUSIONS

There are gaps in the awareness and implementation of GDMT in the diagnosis and treatment of HF in the MEA region. Focused efforts are still needed to improve the basic health care infrastructure in many African countries and to reduce the disparity in availability and accessibility within the health care system. Collection of comprehensive real‐world data through national and regional registries is needed to ascertain the true prevalence of HF, including HFmrEF and HFpEF, for the governments and policy makers to allocate adequate resources to elevate the status of HF care in the MEA region. Enhancing awareness of GDMT among physicians and patients with emphasis on benefits of rapid initiation and strengthening of GDMT drugs in the treatment and prevention of untoward HF outcomes is key to address the gap of underuse of GDMT in the region. Uptake of SGLT2i for treatment and primary prevention of HF in patients with T2D and CKD seems plausible due to SGLT2i’s easy dosing across the HF spectrum. Multidisciplinary approach to HF care is crucial in ensuring seamless integration of GDMT drugs, including SGLT2i, into the clinical practice.

Sources of Funding

AstraZeneca Pharma.

Disclosures

None.

Supporting information

Table S1