Regional expert opinion: Management of heart failure with preserved ejection fraction in the Middle East, North Africa and Turkey

Abstract

Although epidemiological data on heart failure (HF) with preserved ejection fraction (HFpEF) are scarce in the Middle East, North Africa and Turkey (MENAT) region, Lancet Global Burden of Disease estimated the prevalence of HF in the MENAT region in 2019 to be 0.78%, versus 0.71% globally. There is also a high incidence of HFpEF risk factors and co‐morbidities in the region, including coronary artery disease, diabetes, obesity, hypertension, anaemia and chronic kidney disease. For instance, 14.5–16.2% of adults in the region reportedly have diabetes, versus 7.0% in Europe. Together with increasing life expectancy, this may contribute towards a higher burden of HFpEF in the region than currently reported. This paper aims to describe the epidemiology and burden of HFpEF in the MENAT region, including unique risk factors and co‐morbidities. It highlights challenges with diagnosing HFpEF, such as the prioritization of HF with reduced ejection fraction (HFrEF), the specific profile of HFpEF patients in the region and barriers to effective management associated with the healthcare system. Guidance is given on the diagnosis, prevention and management of HFpEF, including the emerging role of sodium‐glucose co‐transporter‐2 inhibitors. Given the high burden of HFpEF coupled with the fact that its prevalence is likely to be underestimated, healthcare professionals need to be alert to its signs and symptoms and to manage patients accordingly. Historically, HFpEF treatments have focused on managing co‐morbidities and symptoms, but new agents are now available with proven effects on outcomes in patients with HFpEF.

Introduction

Globally, heart failure (HF) is estimated to affect the lives of 64.3 million people¹ and is the primary cause of hospitalization in people aged >65 years.² HF also has a considerable impact on quality of life (QoL), being associated with fear of hospitalization, reduced ability to leave home, symptoms such as fatigue and shortness of breath, as well as loss of appetite.³

The Lancet Global Burden of Disease (GBD), the most comprehensive global epidemiological study conducted to date (204 countries; 1990 to 2019), estimated the age-standardized prevalence of HF worldwide to be 0.71% (56.2 million cases) in 2019.^4,5 Although estimates from countries in the Middle East, North Africa and Turkey (MENAT) region are scarce in the literature, the 2019 Lancet GBD estimated that the MENAT region has the fifth-highest prevalence of HF (0.78%), behind high-income North America (1.15%), East Asia (1.01%), Oceania (0.83%) and Eastern sub-Saharan Africa (0.81%).⁵ In the MENAT region, the highest prevalence is seen in Kuwait (1.00%; Table 1).⁴

Table 1 The estimated prevalence of HF in the MENAT region

Region	Countrya	Estimated HF prevalence in 2019 (%)4,5b	Proportion of HF cases that are HFmrEF/HFpEF (%)
Global		0.71	10.0–256c/~507d
Middle East	Kuwait	1.00	13.3–418,9e
Jordan	0.95
Lebanon	0.89
Iran	0.89
UAE	0.87
Qatar	0.83
Iraq	0.81
Saudi Arabia	0.78
Bahrain	0.78
Syria	0.77
Oman	0.77
Yemen	0.75
Cyprus	0.46
Israel	0.33
	Turkey	0.68	9.7c/33.310d
North Africa	Libya	0.89	22.0–758,9e
Tunisia	0.83
Algeria	0.81
Sudan	0.79
Morocco	0.78
Egypt	0.77
Western Sahara	N/Af

The burden of co-morbidity in patients with HF is also typically higher in the MENAT region compared with the Western world. This may in part be due to the increased prevalence of diseases that increase the risk of HF in the region, such as diabetes, obesity and coronary artery disease (CAD).¹ For example, diabetes is present in 50–64% of patients with HF in the Middle East, compared with 31.1–44% in the USA and Europe.^11-14 Renal failure and anaemia are also burdensome co-morbidities with a prevalence of ~25% and ~20%, respectively, in patients with HF in the Middle East.⁸

Although the higher burden of co-morbidity could be expected to translate into higher mortality in the MENAT countries, the available evidence presents a mixed picture. In the International Congestive Heart Failure (INTER-CHF) prospective cohort study, which involved almost 4000 patients from six geographical regions, all-cause mortality in patients with HF after 1 year was lowest in the Middle East (9.4%) and highest in Africa (33.6%).^1,13 The same pattern was also true for cardiac-related deaths.¹³ In another study in the Middle East and Egypt, in-hospital mortality was estimated at ~5% for patients with HF,^15,16 comparable to that of hospitalized HF patients from the ESC-EORP-HFA HF long-term registry in Europe.¹⁷ However, several studies suggest that outcomes are worse in certain countries of the MENAT region; for example, in Yemen, in-hospital mortality is estimated at 9.0%.¹⁸ Hospital readmission rates are particularly high in Egypt, with 29.8% of patients being re-hospitalized for HF at 1 year, compared with 25.6% of patients from Europe.^15,17 Poor survival of previously hospitalized Egyptian HF patients is also of concern, with mortality at 1 year estimated at 26.6%, compared with 22.2% of European patients.^15,17

HF is also a major driver of healthcare costs in the MENAT region, with an estimated 1.35 million patients being treated for HF in Egypt, Saudi Arabia and the United Arab Emirates.¹⁹ Inpatient admission costs account for a high proportion of the burden, ranging from 25–56% of the total estimated cost of US $1.9 billion.¹⁹ A pilot cost analysis study in Egypt revealed that, at the start of 2016, the average HF inpatient cost per day was $55.2 and the average cost per hospital admission was $721.8.²⁰ During a DELPHI panel in Turkey, the total annual national economic burden of HF in terms of direct costs was calculated at 1.4 billion Turkish lira.²¹ Additionally, indirect costs through morbidity, unpaid care, premature mortality and lost productivity also contribute to the financial burden of HF.²¹

HF patients are most often categorized according to left ventricular ejection fraction (LVEF), with patients either having HF with reduced ejection fraction (HFrEF; LVEF ≤40%), mildly reduced ejection fraction (HFmrEF; LVEF 41–49%), or preserved ejection fraction (HFpEF; LVEF ≥50%).³⁴ This paper will focus on the less well-understood HFpEF, which accounts for ∼50% of all HF cases.²²

Burden and epidemiology of heart failure with preserved ejection fraction in the Middle East, North Africa and Turkey region

Burden

HFpEF is associated with a high rate of morbidity and mortality, and patient survival is typically poor. Analysis of data from the Egyptian cohort in the European Society of Cardiology (ESC) HF long-term registry (ESC-HF-LT-R) revealed that patients who were hospitalized for acute HFpEF had a 1-year mortality rate of 19.4%.²³ According to the Gulf CARE registry, which enrolled patients hospitalized for acute HFpEF in the Arabian Gulf, 1-year mortality was lower at 8.1%; however, 1-year HF hospitalization rates were high at 27%.²⁴

Much of the burden related to HFpEF can typically be attributed to a high prevalence of co-morbidities, such as diabetes, obesity, hypertension, anaemia, chronic kidney disease (CKD), atrial fibrillation (AF) and chronic obstructive pulmonary disease (COPD) (Table 2).^1,9,23–29 Patients with HFpEF often have poor QoL, similar to patients with end-stage renal disease, and have substantial limitations to their daily activities.^22,30 However, despite the established negative effect on QoL, variability exists in how these co-morbidities can affect patient outcomes. For example, data from a large registry study in the Middle East showed no difference in mortality or rehospitalization rates between patients with HFpEF with or without diabetes.^31,32

Table 2 Demographics, characteristics and co-morbid conditions of patients with HFpEF enrolled in registries in the MENAT region

Registry	I PREFER9	HEARTS (acute)25	Gulf CARE (acute)24	APOLLON26	Single-centre registry (acute)27	ESC-HF-LT-R (acute)23	NATURE-HF (chronic)28	NATURE-HF (acute)28
Region	Middle East	North Africa	Saudi Arabia	Bahrain, Oman, Qatar, UAE, Kuwait, Saudi Arabia, and Yemen	Turkey	Egypt	Tunisia
HFpEF definition	LVEF ≥45%	LVEF ≥45%	LVEF ≥50%	LVEF ≥50%	LVEF ≥50%		LVEF ≥50%	LVEF >50%	LVEF >50%
Patients, N	203	648	675	932	819	45	~201	97	30
Age, mean ± SD or median (IQR)	63 ± 12	63 ± 12	64.3 ± 13.9	62 (50–72)	67 (IQR unavailable)	52.3 ± 11	58 ± 12	64.8 ± 14.5	67.4 ± 12.4
Female (%)	40	47	52.1	60.0	57.8	100	57.2	49.5	50.0
BMI (kg/m2), mean ± SD or median (IQR)			31.5 ± 8.3	28 (24⁠–33)			32.6 ± 6.2
NT-proBNP (pg/mL), median (IQR)				2209 (816–4646)
Smoker or ex-smoker (%)	42	31	22.7	13.7	15.8		35.8	15.9	23.3
Co-morbid conditionsa
Hypertension (%)	79	76	78.3	64.5	76.1	24.4	42.3	47.4	70.0
Dyslipidaemia, including hyperlipidaemia (%)	66	44	43.7	34.7
CAD (%)	63	50	46.6	43.2	33.1			24.7	23.3
Anaemia (%)			52.2		34.8				36.7
COPD (%)	16	10			13.2		14.9
AF or history of AF (%)	28	34		17.1	38.2	26.6	40.8	35.8	56.7
Chronic renal insufficiency, renal dysfunction, CKD or dialysis (%)			30.9	17.6	10.7		45.5	26.6
Diabetes (%)	45	42	67.8	51.0	29.8		32.3	35.1	40.0
Chronic lung disease (%)			10.6
Cellulitis (%)						13.0
Liver failure (%)						13.3
Obesity (%)	44	43
Myocardial infarction (%)	34	20
Valvular heart disease (%)	32	31
Aetiology of HFpEFb
Ischaemic (%)					21.9		37.8
Arrythmias, including AF (%)				9.5	30.4
Hypertension (%)				11.9	30.6
Valvular disease (%)					13.1
ACS (%)				20.2
Anaemia (%)				3.6
Infection (%)				19.5
Noncompliance with diet or medications (%)				15.9
Worsening renal failure (%)				6.2

Epidemiology

The prevalence of HFpEF amongst patients with new-onset HF has increased in recent decades, with the Framingham Heart Study highlighting an increase from 41.0% in 1985–1994, to 56.2% in 2005–2014 (P < 0.001).³³ Conversely, the prevalence of HFmrEF has remained unchanged across these periods (14.9% vs. 12.8% (P = 0.66)).³³ The increased prevalence of HFpEF has been largely attributed to an increased awareness of HFpEF and changing trends in risk factors for left ventricular systolic dysfunction and HF, in particular a decline in the prevalence of CAD and rising hypertension rates.³³

While there is a good understanding of the epidemiology of HF in the Western world, a lack of data from developing countries has historically made it difficult to estimate the prevalence of HFpEF in the MENAT region.⁸ For example, accurate estimates are not available for North Africa and the Middle East, due to a lack of population-based studies. Recently, comprehensive HF registries have provided new insights into the prevalence of HFpEF amongst patients with HF in the MENAT region, though estimates vary considerably (Table 1). The prevalence of HFpEF in the Middle East is likely to be significantly underestimated, due in part to barriers to diagnosis, which are discussed in more detail below.

Heart failure with preserved ejection fraction risk factors and co-morbidities in the Middle East, North Africa and Turkey region

In general, HF risk factors and co-morbidities can include, but are not limited to, CAD, hypertension, obesity, diabetes, valve disease, arrhythmias, cardiomyopathies, congenital heart disease, some infections, drug use (including some medications, alcohol and cigarette smoking), sleep apnoea, CKD and anaemia.³⁴ However, risk factors and co-morbidities vary between different types of HF. In the MENAT region, compared with HFrEF, patients with HFpEF tend to be older, more often female and obese, more likely to have a history of hypertension, AF and respiratory disease, and less likely to have a history of myocardial infarction.^9,35–39

In the MENAT region, patients with HFpEF typically have a different profile of risk factors and co-morbidities compared with those outside the region. The demographics, characteristics and co-morbid conditions of patients with HFpEF in the MENAT region have been recorded in various registries and are summarized in Table 2.

Diabetes, obesity, hypertension and metabolic syndrome are particularly prevalent in the MENAT countries.^40-43 For example, 16.2% of adults aged 20–79 years in the Middle East and North Africa have diabetes, with Egypt (20.9%), Sudan (18.9%) and Saudi Arabia (18.7%) having the highest prevalence rates.⁴⁰ In Turkey, there is also a higher prevalence of diabetes compared with the rest of Europe, estimated at 14.5% of adults (vs. 7.0% in Europe).⁴⁰ Despite diabetes being prevalent in the MENAT region, diagnosis of co-morbid HF in this high-risk population is poor. In the DISCOVER study programme, 2994 patients with type 2 diabetes (T2D) from the Middle East and Africa were enrolled.⁴⁴ Although macrovascular complications were recorded in 9.8% of these patients, only 1.0% were diagnosed with HF, which is lower than expected.⁴⁴

The prevalence of obesity is rapidly increasing in the Middle East, partly due to socioeconomic transition and increased consumption of high-calorie meals.^8,45 In Middle Eastern countries, pooled estimates for the prevalence of obesity and being overweight are 21.2% and 33.1%, respectively, with the prevalence of obesity increasing with age.⁴¹ In Turkey and several African countries, the prevalence of obesity is consistent with that seen in high-income countries [e.g. Libya (32.5%), Turkey (32.1%) and Egypt (32.0%)].⁴⁶ Of note, the prevalence of obesity is higher in females than in males in most countries of the MENAT region.⁴⁷

Both diabetes and obesity are linked to the development and progression of “diabetic cardiomyopathy”, defined as ventricular dysfunction in the absence of CAD and hypertension.⁴⁸ Given the high prevalence of diabetes and obesity in the MENAT region, diabetic cardiomyopathy is likely to be a common cause of HFpEF here.

Hypertension is also common in the region, with a pooled prevalence of 24.4% of adults >15 years of age in the Middle East.⁴² In patients with HF from the Middle East, the prevalence of hypertension rises to 61–71%.⁸ In Turkey, approximately one-third of adults have hypertension.⁴⁹ Similarly, in Northern Africa, the pooled prevalence of hypertension is estimated to be 33.3%, highlighting it as a significant risk factor for HFpEF in the region.⁵⁰ Tobacco use is also prevalent, with 45.4–49.9% of adult males in Morocco and Egypt and 31.6% of adults in Turkey reported to be smokers.^51,52 In particular, countries within the Arabian Gulf have a high incidence of risk factors for HFpEF, with smoking levels and rice consumption amongst the highest in the world.⁸

Data from the 2019 Lancet GBD study highlight that anaemia, COPD and CKD are also burdensome HFpEF risk factors/co-morbidities in the MENAT region.^53-57 The age-standardized prevalence of anaemia in the MENAT region (per 100 000 population) was estimated to be 18 019.7 [95% uncertainty interval (UI): 17 398.5–18 738.9]. Although this rate is comparable with other regions of similar socio-economic status, it is much higher than in regions with a higher socio-economic status.⁵³

The highest age-standardized prevalence of COPD in the MENAT region (per 100 000 population) was found in Turkey [(3287.1 (95% UI: 3187.4–3380.3)], followed by the United Arab Emirates [2926.9 (95% UI: 2811.1–3046.4)].⁵⁴ This is higher than the global prevalence [2638.2 (95% UI: 2492.2–2796.1)].⁵⁵ However, the prevalence of COPD was slightly lower in the MENAT region as a whole [2333.9 (95% UI: 2230.1–2443.6)].⁵⁴

CKD is also a prevalent co-morbidity, with an estimated age-standardized prevalence (per 100 000 population) of 10 589.7 in the MENAT region (95% UI: 9930.4–11 229.5).⁵⁶ This is significantly higher than the global prevalence [95% UI: 8596.2 (8015.7–9125.3)].⁵⁷

Challenges with diagnosis of heart failure with preserved ejection fraction in the Middle East, North Africa and Turkey region

Difficulties with diagnosing HFpEF may partly explain why its prevalence is likely to be underestimated. Reasons for the inadequate detection of HFpEF may include (i) the diagnostic system prioritizing HFrEF; (ii) the different profiles of HFpEF patients in the MENAT region; (iii) poor healthcare infrastructure.

Prioritization of heart failure with reduced ejection fraction over heart failure with preserved ejection fraction diagnosis

Unlike HFrEF, no standard definition for HFpEF exists, meaning that it is inconsistently identified by healthcare professionals (HCPs). The HF diagnostic system is optimized to primarily identify patients with the more easily recognizable HFrEF. Specifically, when diagnosing HF, HCPs will often look for a reduction in ejection fraction, as seen in HFrEF. For patients with HFpEF who have a near-normal ejection fraction, the possibility of HFpEF is sometimes ignored.^58,59

Similarly, reliance solely on B-type natriuretic peptide (BNP) as a diagnostic marker in the outpatient setting can miss ~30% of HFpEF cases.⁶⁰ This may be because BNP levels are often not sufficiently elevated to signify the presence of HFpEF in patients with obesity. As there is a high prevalence of obesity across the MENAT region, the poor reliability of this diagnostic test is problematic. However, the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) 2022 and ESC 2021 guidelines now recommend a lower natriuretic peptide (NP) threshold (>35 pg/mL for BNP and >125 pg/mL for NT-proBNP) to increase the sensitivity of detection in the outpatient setting.^34,61

Additionally, the poor representation of HFpEF in HF registries, particularly those conducted in the MENAT region, contributes to a lack of representative data for HFpEF. As such, many HCPs do not have a good understanding of how HFpEF differs in patients from their region.

The different profile of heart failure with preserved ejection fraction patients in the Middle East, North Africa and Turkey region

In the MENAT region, patients with HFpEF tend to be younger than their Western counterparts.^{23,24,36,38,62} For example, in the Middle East and Egypt, patients are at least 10 years younger on average,^15,63 in part due to the early incidence and high prevalence of risk factors such as obesity, diabetes, hypertension and CAD.^1,8,15 For instance, premature ACS is highly prevalent in Egypt, and this is to some extent due to limited access to CAD primary and secondary prevention strategies.¹⁵ Hence, these younger individuals frequently do not fit the commonly accepted phenotype of the average elderly patient with HF and may be missed.

HFpEF symptoms are often non-specific, and may be mistaken for signs of ageing or co-morbidities such as anaemia, CKD or COPD.⁶⁰ As many patients with HFpEF from the MENAT region have a higher burden of co-morbidities, their primary diagnosis of HF is more likely to be missed or misclassified. These co-morbid patients are often admitted to services other than cardiology and may receive different primary diagnoses.

Poor healthcare infrastructure

Most patients within the MENAT region are only looked after by primary care physicians, who often focus on treating the primary risk factors of HFpEF without considering that the patient may already have HFpEF. Patients with HFpEF are not always referred to the correct department, which can ultimately delay diagnosis. For patients who are referred, a lack of HF specialists in the region means that patients are often directed to unspecialized cardiologists.

Poor healthcare infrastructure and a lack of diagnostic tools also contribute to difficulties with diagnosing HFpEF. Many countries in this region do not have access to sophisticated diagnostic techniques. For instance, only 0.3% of hospitalized patients from the ESC-HF-LT-R Egyptian cohort were assessed using cardiac computed tomography and right heart catheterization.⁶² Despite some variation in the use of diagnostic modalities for HF in the Middle East and Turkey, electrocardiograms (ECGs) and echocardiograms are commonly used.^62,63 Access to echocardiography is particularly widespread in the Arabian Gulf, where it is used in nearly 97% of the HF population in Saudi Arabia, and ~93% in other Gulf countries.⁸ Similarly, a task force report conducted in 2018 found that ECGs and echocardiograms are widely available in North Africa, although mainly in secondary and tertiary health facilities in larger cities.⁶⁴ This report also found that although ambulatory ECG monitoring and exercise treadmill testing are available in North Africa, these tests are very expensive. Measurement of NP levels and cardiac magnetic resonance imaging are not available in all cardiac service centres in these regions. This is mostly due to unavailability of equipment and qualified technicians, lack of availability and reimbursement of expensive NP testing kits, and a lack of knowledge about the importance of NPs as a diagnostic marker.^8,62,63 In the I PREFER registry, which included patients from both the Middle East and North Africa, only 3.8% of all patients were recognized to have had measurement of BNP concentrations.⁹ Similarly, none and very few patients from Egypt enrolled in the DELTA-HF registry or the ESC-HF-LT-R, respectively, had undergone NP testing.^62,65 Despite being a part of the international HF recommendations, only a few countries, particularly in the Arabian Gulf, have specific HF programmes with specialized HF clinics run by certified HF cardiologists with the support of nurses, pharmacists and other disciplines.⁸

Guidance for the diagnosis of heart failure with preserved ejection fraction in the Middle East, North Africa and Turkey region

Two score-based algorithms (HFA-PEFF and H₂FPEF) are available to help diagnose HFpEF,^58,66 though both have demonstrated diagnostic variability.³⁴ The H₂FPEF score, calculated from basic clinical and echocardiographic information, is suitable for general practitioners and non-cardiologist specialist physicians,⁶⁷ whereas calculation of the HFA-PEFF score requires detailed echocardiography and NP testing, carried out by a cardiologist.^58,66 Regardless of the scoring system used, patients often need to be referred for additional confirmatory tests, which may not always be available within the MENAT region. This makes the diagnosis of HFpEF in the region particularly challenging.³⁴

In the recent 2021 ESC guidelines, a simplified diagnostic algorithm was proposed which emphasizes the most frequently used variables commonly available to clinicians worldwide (e.g. echocardiography).³⁴ Following this algorithm, the diagnosis of HFpEF should include signs and symptoms of HF, an LVEF ≥50%, and objective evidence of cardiac structural and/or functional abnormalities suggestive of LV diastolic dysfunction or raised LV filling pressures [LV mass index ≥95 g/m² (female) and ≥115 g/m² (male); relative wall thickness >0.42; left atrial volume index >34 mL/m² (SR) or >40 mL/m² (AF); E/e′ (early filling velocity on transmitral Doppler/early relaxation velocity on tissue Doppler) ratio at rest >9; pulmonary artery systolic pressure >35 mmHg; and tricuspid regurgitation velocity at rest >2.8 m/s]. In cases of diagnostic uncertainty, the approach to diagnosis should involve additional confirmatory tests, such as exercise stress testing and invasive haemodynamic testing. However, as it is recognized that many of these additional tests are not available worldwide, the ESC guidelines do not require gold-standard testing to make a diagnosis of HFpEF. Instead, the greater the number of objective non-invasive markers of raised LV filling pressures, the higher the likelihood of a HFpEF diagnosis. Guidelines developed for non-cardiac specialties also offer useful practical advice. For example, the American Diabetes Association recommends annual NP or cardiac troponin measurements amongst individuals with diabetes to identify early HF and implement strategies to prevent transition to symptomatic HF.⁶⁸

Management of heart failure with preserved ejection fraction in the Middle East, North Africa and Turkey region

Prevention of heart failure with preserved ejection fraction

The optimal strategy to prevent HFpEF is to avoid or carefully manage risk factors.^34,61 One of the most prevalent risk factors for HFpEF in the MENAT region is diabetes, and people with T2D are reportedly 2.5 times more likely to develop HF than those without the condition.⁶⁹ As such, there is a great focus on treatments with the potential to prevent HF in patients with diabetes. Regional observational studies such as DISCOVER ME⁷⁰ and PACT MEA⁷¹ have shown that glucose-lowering agents such as sulfonylureas, thiazolidinediones and insulin are often used in the MENAT region. However, these therapies are associated with adverse cardiovascular outcomes, such as an increased risk of incident HF and an increase in mortality and hospitalizations associated with HF.^69,72

While some glucose-lowering agents have a good cardiovascular safety profile in patients with T2D, sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin and dapagliflozin may also prevent incident HF in at-risk patients with diabetes.⁷³ In the EMPA-REG OUTCOME TRIAL,⁷⁴ patients with T2D and high cardiovascular risk were randomized to receive empagliflozin or placebo alongside background diabetes therapy. Empagliflozin reduced the primary outcome (composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke) as well as decreasing all-cause death and hospitalization for HF compared with placebo.⁷⁴ Similarly, the SGLT2 inhibitors dapagliflozin, canagliflozin and ertugliflozin were shown to reduce hospitalization for HF in the DECLARE-TIMI, CANVAS and VERTIS-CV trials, respectively.^75-77 Hence, several SGLT2 inhibitors are recommended in the AHA/ACC/HFSA 2022 and ESC 2021 HF guidelines for patients with T2D at high risk of cardiovascular disease, or with cardiovascular disease to prevent HF hospitalizations.^34,61

Treatment of heart failure with preserved ejection fraction

Historically, management of HFpEF has proven to be much more difficult than that of its counterpart, HFrEF. The heterogeneity of risk factors for HFpEF and the multifactorial nature of its pathophysiology makes it difficult to target the dominant components in different subgroups of patients. Given these challenges, treatments have focused predominantly on managing co-morbidities and controlling symptoms. Due to the high prevalence of hypertension and CAD in patients with HFpEF, particularly those in the MENAT region, many patients are treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, or mineralocorticoid receptor antagonists (MRAs).³⁴ Diuretics are also recommended to alleviate symptoms of congestion.³⁴

Most treatments under investigation for the treatment of HFpEF in clinical trials (e.g. perindopril, candesartan, irbesartan, spironolactone, digoxin and sacubitril/valsartan) have only demonstrated a modest ability to reduce mortality and morbidity in patients with HFpEF.^78–83 However, improvements have been observed in specific subcohorts of patients with HFpEF or HFmrEF. For example, both the MRA spironolactone and the ARB candesartan have been shown to reduce cardiovascular death and HF hospitalizations in patients with low baseline LVEF.^84,85 The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan also reduced cardiovascular death and hospitalizations in patients with an LVEF ≤57% compared with renin-angiotensin-aldosterone-system inhibitors.^83,86 These benefits were found to extend to a higher LVEF in women compared with men.⁸⁶

Based on the results of these analyses, the US Food and Drug Administration (FDA) endorsed the use of sacubitril/valsartan and spironolactone in patients with a ‘less than normal’ LVEF, encompassing both HFmrEF and HFpEF patients.³⁴

Sodium-glucose co-transporter-2 inhibitors for the treatment of heart failure with preserved ejection fraction

In recent years, SGLT2 inhibitors have emerged as important therapies for HF, although their use has previously been reserved for patients with HFrEF. Positive results from the EMPEROR-Reduced⁸⁷ and DAPA-HF⁸⁸ trials led to the FDA and European Medicines Agency (EMA) approving empagliflozin and dapagliflozin to reduce the risk of HF hospitalization and death in patients with HFrEF, regardless of diabetes status.^89-92 However, findings from the EMPEROR-Preserved trial⁹³ have prompted the FDA and EMA to expand the indication of empagliflozin to also include patients with HFpEF or HFmrEF.^94,95 Similarly, recently published findings from the DELIVER trial⁹⁶ have also led the FDA and EMA to expand the indication of dapagliflozin to cover these subtypes.^92,93

The SGLT2 inhibitor empagliflozin has been found to reduce the combined risk of cardiovascular death or HF hospitalization (primary outcome) in patients with HFmrEF/HFpEF in the Phase III, double-blind, randomized EMPEROR-Preserved trial.^94,98,99 This effect was observed regardless of the presence or absence of diabetes.⁹⁴ Over a median of 26.2 months, the primary outcome occurred in 13.8% of patients in the empagliflozin group and 17.1% of patients in the placebo group [hazard ratio 0.8; 95% confidence interval (CI): 0.7–0.9; P < 0.001].⁹⁴ Secondary analyses of data from EMPEROR-Preserved have recently shown that empagliflozin can reduce cardiovascular death or hospitalization for HF in patients with HFpEF or HFmrEF, regardless of age, the presence or absence of AF, body mass index, or baseline systolic blood pressure (BP).^100–103

The effectiveness of empagliflozin in the EMPEROR-Preserved trial has called into question whether other SGLT2 inhibitors could have similar beneficial effects in the HFpEF/HFmrEF patient populations. The SGLT2 inhibitor dapagliflozin has recently been found to reduce the risk of cardiovascular death and worsening HF (HF hospitalization or urgent HF visit; primary composite outcome) in patients with HFmrEF/HFpEF in the Phase III, double-blind, randomized DELIVER trial.¹⁰⁴ Over a median of 2.3 years, the primary composite outcome occurred in 16.4% of patients in the dapagliflozin group and in 19.5% of patients in the placebo group (hazard ratio 0.8; 95% CI: 0.7–0.9; P < 0.001). The effect of dapagliflozin was consistent across all prespecified subgroups, being unaffected by variables such as age, the presence or absence of T2D or AF, body mass index, estimated glomerular filtration rate (eGFR) at enrolment, systolic BP at randomization, and previous LVEF being ≤40%. Unlike EMPEROR-Preserved, DELIVER included a dual primary analysis, assessing the primary endpoint in both the full population and those with an LVEF <60%.¹⁰⁵ Dapagliflozin reduced the risk of the primary composite outcome compared with placebo, with no appreciable difference in benefit amongst patients with a LVEF ≥60% or <60%.¹⁰⁴ Due to differences in the definition of endpoints between the two trials, comparison of results will be difficult. However, in a sub-analysis of EMPEROR-Preserved data, empagliflozin was found to improve cardiovascular outcomes in patients with HFmrEF/HFpEF, when using the DELIVER endpoint definitions.¹⁰⁶

Use of and adherence to heart failure with preserved ejection fraction medications in the Middle East, North Africa and Turkey region

Although most HF therapies are available for use in patients with HFpEF in the MENAT countries, their use is variable (Table 3). For instance, data from several registries demonstrate that the use of beta-blockers before or at HF hospital or clinic admission can vary from 24.5−90%.^65,108 Throughout this region, the use of angiotensin-converting-enzyme inhibitors (ACEIs)/ARBs, beta-blockers and aldosterone antagonists is typically significantly lower prior to admission than at discharge.^65,108 In the Middle East, the use of evidence-based therapies for HF is widespread, particularly in the Arabian Gulf.⁸ According to the HEARTS and Gulf CARE registries, at the time of hospital/clinic discharge, the use of beta-blockers and ACEIs/ARBs is extensive (72.7–91%), and aldosterone antagonists are used at a rate comparable with the rest of the world (38.2–45%).^8,11,24,108 According to the Gulf RACE registry, the use of beta-blockers is much lower in this region, at 56.0% at hospital discharge.¹⁴ In a study of patients with HF from Yemen, the prescription of HF medications was assessed against AHA recommendations to determine the percentage deviation from the guidelines. The maximum deviation was observed with ARBs (~89%) and beta-blockers (~87%), with a deviation rate of ~27% for ACEIs.¹⁰⁹ The authors propose that inadequacy in prescribing rate may be partly due to HCPs being unaware or unaccepting of new guideline-recommended therapies, as well as patient resistance to medication change. In Egypt and Tunisia, the use of these evidence-based therapies is also variable. For example, the use of ACEIs/ARBs at hospital/clinic discharge can range from 62.0% in patients with acute HF (AHF) in the NATURE-HF registry to 85.8% with AHF in the ESC-HF-LT-R.^28,62 Amongst outpatients with chronic HF (CHF), this increases to 89.8%.⁶² The use of beta-blockers and aldosterone antagonists at discharge can be as low as 50.0% and 17.0%, respectively.^14,65 In Turkey, beta-blockers have been reported to be the most used drugs for HF (75%). Poor use of ACEIs (57%) and ARBs (20%) is also reported here.²¹

Table 3 Prevalence of key HF medications amongst patients with HF enrolled in registries in the MENAT region

Registry	Region	ACEI	ARB	ACEI/ARB (%)	Beta-blocker (%)	Aldosterone antagonist (%)
I PREFER9	Middle East and North Africa	43a	46a		59a	28a
INTER CHF107	Middle East	61.6a	20.0a		85.9a	45.8a
HEARTS (chronic)108	Saudi Arabia			79a/80b/88c	90a/91b/94c	44a/45b/42c
HEARTS (acute)11	Saudi Arabia			68.3a/75.0b	79.0a/84.0b	29.0a/38.2b
Gulf CARE (acute)24	Bahrain, Oman, Qatar, UAE, Kuwait, Saudi Arabia, and Yemen	43.5a/61.8b	12.9a/17.1b		45.0a/72.7b	17.1a/44.7b
Gulf RACE14 (acute)	Bahrain, Oman, Qatar, UAE, Kuwait, Yemen			77.0a/78.0b	40.0a/56.0b	0.0a/17.0b
DELTA-HF (acute)65	Egypt	20.9a/63.3b	10.9a/13.3b		24.5a/50.0b	21.8a/52.2b
ESC-HF-LT-R (acute)62	Egypt			85.8b	65.8b	68.2b
ESC-HF-LT-R (chronic)62	Egypt			89.8a	67.0a	86.4a
Single-centre registry (acute)27	Egypt			64.2a	35.8a	46.6a
NATURE-HF (chronic)28	Tunisia			68.9a/73.2c	67.0a/71.9c	28.8a/31.3c
NATURE-HF (acute)28	Tunisia			62.0b/72.9c	57.4b/68.2c	31.9b/39.7c

Adherence to guideline-directed therapies is considered the greatest predictor of treatment success and hospitalizations.¹¹⁰ However, reports of medication adherence vary considerably in the MENAT region. This may be partly due to factors such as the use of different measurement tools/scales, different sociocultural contexts, and varying disease severities.^111,112 In Iran, poor self-reported HF medication adherence has been reported in 60.3%,¹¹¹ 61.0%¹¹⁰ and 71.4%¹¹³ of patients across three studies. Similarly, in the Aseer region of Saudi Arabia, 53.6% of patients are reported to have low adherence to their HF medications.¹¹⁴ Amongst patients with HF in Yemen, 47.1% and 12.9% were reported to have low or medium adherence to their HF medications, respectively.¹⁰⁹ However, in a study of Moroccan patients with CHF, medication adherence was reportedly high, at 83%.¹¹²

Many variables have been suggested to be associated with poor medication adherence in the MENAT region, such as education level, number of children, number of co-morbidities, duration of treatment, gender, health literacy, depression, level of social support, self-medication and number of tablets per day.^110-112,114 For example, in multivariate analyses of data from Iranian patients with HF, adherence was found to be 3.4-times lower in patients with low health literacy than those with borderline health literacy.¹¹⁰ Inadequate health literacy has been reported amongst the Iranian population and was detected in 74% of patients in the study.^110,115 Similarly, a study of Moroccans with CHF revealed that 50% of patients had insufficient knowledge about their medications.¹¹² Poor medication adherence in the MENAT region is concerning, as this can minimize therapeutic effectiveness and lead to the clinical deterioration of patients.^110,114 Ultimately, this will increase costs for patients and will place an even greater strain on healthcare systems in a region which are already struggling against the rising burden of chronic diseases.

Expert consensus: Treatment recommendations for heart failure with preserved ejection fraction in the Mid region

Expert consensus regarding recommendations for the treatment of HFpEF in the MENAT region is described below. Recommendations are based on the latest data and guidelines and take into consideration regional factors.

Initiating therapy

To reduce HF hospitalizations and cardiovascular mortality, patients with HFpEF should first be initiated on the SGLT2 inhibitor empagliflozin, as per the AHA/ACC/HFSA 2022 HF guidelines.⁶¹ This recommendation should extend to patients who present with acute decompensated HFpEF in a clinical setting. Results from the EMPULSE study suggest that an earlier initiation of empagliflozin in patients hospitalized for AHF can result in significant clinical benefit. More patients treated with empagliflozin had clinical benefit (defined as a composite of all-cause mortality, number and time to first HF event, and change in the Kansas City Cardiomyopathy Questionnaire total symptom score) compared with placebo (stratified win ratio, 1.4; 95% CI: 1.1–1.7; P = 0.0054) after 90 days, meeting the primary endpoint.¹¹⁶ Given the recently published positive results from the DELIVER trial, it is expected that guidelines will soon be updated to also recommend dapagliflozin for patients with HFpEF.¹⁰⁴ Dapagliflozin reduced the combined risk of worsening HF or cardiovascular death regardless of whether patients were enrolled during or within 30 days after hospitalization for HF, or enrolled outside of this window. As such, the recommendation to initiate treatment with an SGLT2 inhibitor is likely to extend to include dapagliflozin as a possible initiating therapy.

Additional or alternative therapy

If symptoms persist while taking a SGLT2 inhibitor, the addition of an MRA should be considered to reduce cardiovascular death and hospitalization. However, specialist advice should be sought out before considering MRAs for patients with significant hyperkalaemia (K⁺ > 5.0 mmol/L) or significant renal dysfunction (creatinine >2.5 mg/dL).³⁴ The use of MRAs will be of most benefit for patients with an LVEF closer to 50%.⁶¹

Patients with HFpEF who fit the criteria identified from a prespecified subgroup analysis of the PARAGON trial (female with an LVEF ≤57%) may benefit from additional treatment with sacubitril/valsartan.^61,83 Sacubitril/valsartan should be added to the treatment regimen if these PARAGON-positive patients are frequently hospitalized, or experience New York Heart Association ≥class II symptoms despite treatment with the above therapies.

In the absence of recommendations for disease-modifying therapies, symptom control should be prioritized. In patients with HFpEF who have evidence of fluid retention, diuretics should be prescribed to reduce congestion, improve symptoms, and prevent worsening HF.⁶¹ Loop diuretics are recommended, although thiazide diuretics may be preferred for patients with co-morbid hypertension.³⁴

Treatment of co-morbid heart fail

Therapeutic recommendations for HFpEF will also depend on the co-morbidities that each patient has, as detailed below.

HFpEF with co-morbid CKD

HFpEF and CKD frequently co-exist, partly due to common risk factors, such as hypertension and diabetes.¹¹⁷ Complex bidirectional interactions occur between the heart and kidneys, whereby the dysfunction of one organ can induce dysfunction in the other.¹¹⁸ Macrovascular changes associated with CKD and several renal factors are thought to contribute to the development of HF.¹¹⁷ In turn, HF can lead to kidney dysfunction and increase the risk of CKD.¹¹⁸

Patients with co-morbid CKD have a particularly high risk for cardiovascular death or HF hospitalization.¹¹⁹ The treatment of patients with this profile is often difficult, as renal dysfunction can diminish the response to diuretics and increase the toxicity risk of most HF therapies.⁶¹ Several HF therapies can also exacerbate renal dysfunction and must be administered cautiously.¹²⁰

SGLT2 inhibitors and sacubitril/valsartan should be considered in patients with HFpEF with co-morbid CKD and an eGFR >30 mL/min/1.73 m². Of note, 49.9% of patients participating in the EMPEROR-Preserved trial had an eGFR <60 mL/min/1.73 m² (prevalent CKD).⁹³ Furthermore, in patients with CKD in EMPEROR-Preserved, empagliflozin reduced the risk of cardiovascular death and hospitalization for HF by 20.0% and reduced total hospitalizations for HF by 32.0%.¹²¹ Similarly, in the DELIVER trial, dapagliflozin reduced the risk of worsening HF or cardiovascular death by 19.0% in patients with CKD.¹⁰⁴ Empagliflozin also slowed the yearly decline in eGFR by 1.43 mL/min/1.73 m² (1.01−1.85) in patients with CKD.^121,122 Similarly, sacubitril/valsartan also slowed the decline in kidney function associated with CKD in the PARAGON-HF and PARAMOUNT trials.¹¹⁹ The benefit of empagliflozin extends to patients with CKD and an eGFR of 20–30 mL/min/1.73 m², making it the preferred choice for patients with this profile.¹¹⁹

Heart failure with preserved ejection fraction with co-morbid obesity

To alleviate symptoms and improve exercise capacity, exercise and weight loss is recommended for patients with HFpEF who are obese.³⁴

HFpEF with co-morbid hypertension

Diuretics and MRAs can be used for the initial treatment of hypertension among patients who do not have a compelling indication for a specific antihypertensive therapy.⁶¹ Medication should be titrated to attain BP targets and prevent morbidity.⁶¹ The ACC/AHA/HFSA HF guidelines recommend a systolic BP target of less than 130 mmHg for patients with HFpEF and persistent hypertension.^61,123 If the BP goal is not reached despite maximum tolerated doses, antihypertensive agents such as sacubitril/valsartan, an ARB, or calcium channel blockers should be initiated.

Heart failure with preserved ejection fraction with co-morbid atrial fibrilation

Management of AF may be recommended to improve HFpEF symptoms.⁶¹ Patients with HFpEF and AF should be managed according to clinical practice guidelines that apply to all patients with HF. Specifically, patients with CHF with permanent-persistent-paroxysmal AF and a CHA₂DS₂-VASc (congestive HF, hypertension, age ≥75 years, diabetes, stroke or transient ischemic attack, vascular disease, aged 65–74 years, sex category) score of ≥2 for men and ≥3 for women should be given chronic anticoagulant therapy.⁶¹ Direct-acting oral coagulants are typically preferred over warfarin. AF ablation may also be beneficial for patients with symptomatic AF.⁶¹

Heart failure with preserved ejection fraction with co-morbid diabetes

In patients with HFpEF and T2D, empagliflozin is recommended to manage hyperglycaemia.⁶¹ This recommendation will likely extend to include dapagliflozin, given that its ability to reduce the combined risk of worsening HF or cardiovascular death in patients with HFmrEF or HFpEF was observed regardless of the presence or absence of T2D.¹⁰⁴

Cost considerations

Sacubitril/valsartan and SLGT2 inhibitors are typically more expensive than other HF therapies.¹²⁴ For many patients in the MENAT region, the out-of-pocket costs for these therapies may not be affordable, particularly if these treatments were to be prescribed in combination. For instance, the high cost of sacubitril/valsartan in the Middle East, and the limited experience that HCPs have with this treatment, limits its use.⁸ In Egypt, sacubitril/valsartan is five times more expensive than the most expensive SLGT2 inhibitor. However, the country's national health insurance provides sacubitril/valsartan for patients who are insured.¹²⁴ In cases such as this, sacubitril/valsartan may be preferred.¹²⁴

Patient follow-up

Patients with HFpEF must be followed up regularly to ensure optimization of therapy and to monitor disease progression. The extent of follow-up should depend upon symptom severity, co-morbid conditions, whether the patient has recently been discharged from hospital, and whether the patient is undergoing medication up-titration.³⁴

During follow-up, heart rate and rhythm, BP, full blood count, electrolytes, and renal function should be assessed.³⁴ For patients showing signs of decompensation, an echocardiogram should also be carried out to assess diastolic parameters.³⁴ An evaluation of NP levels and a chest x-ray may also be beneficial. Patients with evidence of worsening HF should be re-referred to a cardiologist.

To improve patient retention, patient education surrounding the importance of symptom follow-up is needed at each visit. Patients must be informed that even if their LVEF is normal, decompensation is still possible.

Conclusions

Prevalence data on HFpEF are scarce in the MENAT region, due in part to a lack of population based-studies, methodology bias and diagnostic challenges. Hence, its prevalence is likely to be underestimated. There is a high incidence of risk factors and co-morbidities of HFpEF, which together with increasing life expectancy contributes to the high burden of HFpEF. Given the high burden coupled with the fact that it is underestimated, HCPs need to be alert to the signs and symptoms of HFpEF and to manage and refer patients with the condition accordingly. Historically, treatments for HFpEF have focused predominantly on managing co-morbidities and controlling symptoms, but new agents—the SGLT2 inhibitors—are now available with favourable outcomes in patients with HFpEF.

Acknowledgements

Melissa Lawton, MSci, of Meditech Media provided writing support, which was contracted and funded by Boehringer Ingelheim Middle East & North Africa.

Conflict of interest

Bülent Altun has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca and Boehringer Ingelheim; support for attending meetings and/or travel from Abdi İbrahim, AstraZeneca, Bayer, Boehringer Ingelheim and Sanofi. Mohamed Arafah has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca, Merck and Pfizer; support for attending meetings and/or travel from Pfizer. Ahmed Shawky Elserafy has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer and Servier; has participated on a Data Safety Monitoring Board or Advisory Board affiliated with Novartis; has acted as an exam coordinator for the Egyptian Board of Interventional Cardiology Fellowship program. Hadi Skouri has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Abbot, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, Servier and Vifor Pharma. The Faculty of Medicine (Hacettepe University), to which Hadi Skouri is affiliated, has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Abdi İbrahim, Bayer, Boehringer Ingelheim and Sanofia. Dokuz Eylul University, to which Mehmet Birhan Yilmaz, is affiliated has received grants or contracts from Albert Health, Amgen, Bayer, Dalcor Pharmaceuticals and Novartis; his institution has also received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca and Boehringer Ingelheim. Mohamed Ibrahim is an employee at Boehringer Ingelheim and moderated the advisory board that led to the development of this manuscript. Hani Sabbour has received honoraria for advisory boards and as speaker at scientific meetings from Amgen, Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Menarini, Novartis, Pfizer, Sanofi and Servier. Magdy Abdelhamid, Kamal Al Ghalayni, Feras Bader and Khaldoon Al-Humood have nothing to disclose.

Funding

Writing support was funded by Boehringer Ingelheim Middle East & North Africa.

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