Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent subtype of heart failure. It is characterized by a heterogeneous clinical phenotype, a less understood pathophysiology, and multifactorial etiologies. A frequent comorbidity of HFpEF is chronic kidney disease (CKD). The cardiorenal phenotype in HFpEF is growing in prevalence and represents a high-risk clinical population. HFpEF and CKD are interconnected through complex, bidirectional processes involving systemic inflammation, neurohormonal activation, hemodynamic changes, and iron deficiency. These overlapping processes, along with common risk factors, exacerbate disease presentation and progression, contributing to significantly worse outcomes, including higher rates of hospitalization, mortality, and progression to end-stage kidney disease. Historically, treatment options for HFpEF have been limited, but recent studies have identified agents with both cardiovascular and renal benefits. Emerging therapies, such as SGLT2 inhibitors, nonsteroidal MRAs, and GLP-1 receptor agonists, offer a new hope for improving outcomes in the HFpEF cardiorenal population. However, challenges related to diagnosis, volume and potassium management, and barriers such as underdiagnosis and undertreatment still remain. An integrative, multidisciplinary approach is essential for effectively managing patients with both HFpEF and CKD.
Heart failure (HF) is a clinical syndrome universally characterized by typical symptoms and/or signs caused by a structural and/or functional cardiac abnormality, supported by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. Additionally, HF can be classified according to left ventricular ejection fraction (LVEF). HF with preserved EF (HFpEF), one of the subclassifications and the focus of this review is defined as HF with a LVEF ≥50%.
With increasing prevalence, HFpEF currently represents more than 50% of the global HF population. Despite this increase and advances in the last decade, in contrast to HF with reduced EF (LVEF ≤40%), HFpEF remains with more limited evidence-based therapeutic options. This is partly due to its distinct and less understood pathophysiology, multifactorial etiologies, and highly heterogeneous clinical phenotype.
A frequent comorbidity of HFpEF is chronic kidney disease (CKD). The heart and kidney are interconnected through complex pathophysiological pathways that can lead to dysfunction in both systems. The cardiorenal phenotype in HFpEF is growing in prevalence, it poses diagnostic and treatment challenges and is associated with poorer outcomes. An integrative, multidisciplinary approach is essential for effectively managing HFpEF in CKD patients. Therefore, this review addresses the current evidence on the HFpEF and CKD interplay, summarizes shared pathophysiological mechanisms, discusses diagnostic and therapeutic challenges, and outlines available evidence-based therapies to provide a clearer framework for managing the cardiorenal population in HFpEF.
Epidemiology of Patients With HFpEF and CKD
Acquiring epidemiological data on HFpEF and CKD populations can be challenging, as both conditions are often underrepresented in clinical trials, have variable definition criteria, and lack unified databases. The prevalence of CKD among HFpEF patients is high, although it varies across studies. An American observational cohort reported that 48% of HFpEF patients had CKD (using estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 to denote CKD). Other recent studies have reported higher rates of CKD in HFpEF, with 60% in a Belgian cohort and 56% in the Swedish Heart Failure Registry, where CKD was more prevalent in HFpEF than in other HF subtypes. , In fact, the higher incidence of HFpEF compared to HFrEF has been reported across other CKD populations. For instance, in the large CKD cohort of the Kaiser Permanente of Southern California, 59% of patients had HFpEF, while only 23% had HFrEF.
The importance of clinical profiling has been gaining increased recognition, with many studies attempting to define a cardiorenal phenotype. In these studies, the co-occurrence of HFpEF and CKD was associated with advanced age, worse eGFR and the female sex. Furthermore, this cardio-renal population is burdened with multiple comorbidities, including more frequent reports of atrial fibrillation, anemia, and diabetes. ,
The Bidirectional Link Between HFpEF and CKD
Cardiorenal syndrome
The term cardiorenal syndrome (CRS) refers to disorders affecting both the heart and the kidneys, in which acute or chronic dysfunction in 1 organ can induce acute or chronic dysfunction of the other. CRS can be classified into 5 subtypes according to the initiating organ dysfunction and whether it is an acute or chronic event ( Figure 1 ).
The 5 subtypes of cardiorenal syndromes (CRS) and the proposed key pathomechanisms. CRS can be classified into 5 subtypes according to the initiating organ dysfunction– the heart (types 1 and 2), the kidney (types 3 and 4), or systemic (type 5)- and whether it is an acute (types 1 and 3) or chronic (types 2 and 4) event. The arrows indicate the direction of the effect. AKI, acute kidney injury; CKD, chronic kidney disease; HF, heart failure.
The definition and subtypes of CRS were established in 2008 at the consensus conference on CRS of the Acute Dialysis Quality Initiative. This recognition and categorization of the cardiorenal interaction was expected to facilitate future research on the topic and consequently achieve a better understanding and management of CRS.
Although this classification has raised awareness to cardiorenal interactions, it has not been widely adopted in clinical practice, clinical trials, or studies. Assigning patients to a specific category can be difficult due to overlap or uncertainty about which organ was affected first. Furthermore, this classification does not particularly clarify the underlying pathophysiologic mechanisms. Therefore, some authors propose moving towards a CRS model that reflects the clinical expression of the shared pathophysiological pathways and risk factors of heart and kidney disease.
Pathophysiological pathways
The underlying pathophysiology linking HFpEF and CKD is not yet fully understood. Nonetheless, several potential pathways have been suggested and are outlined below and summarized in Figure 2 .
Summary of the pathophysiological pathways linking heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD). HFpEF and CKD exacerbate each other through a pro-inflammatory systemic state, the activation of neurohormonal mediators, a state of volume and pressure overload and hypoperfusion, as well as iron deficiency. Additionally, they share common risk factors that further exacerbate both diseases. The arrows indicate the direction of the effect. CVP = central venous pressure; cGMP = cyclic guanosine monophosphate; FGF23 = fibroblast growth factor 23; GFR = glomerular filtration rate; MR = mineralocorticoid receptor; NO = nitric oxide; PTH = parathyroid hormone; PKG = protein kinase G; ROS = reactive oxygen species.
Some of these proposed pathways may not be exclusive to the relationship between renal impairment and HFpEF, and could also apply to HFrEF.
Inflammation, endothelial dysfunction, and fibrosis
Numerous studies have found increased levels of inflammatory markers in patients with HFpEF, suggesting a strong association between inflammation and HFpEF. For example, interleukin-6 and tumor necrosis factor-α were strongly linked to the risk of developing new-onset HFpEF, even more so than the risk of new-onset HFrEF. This systemic proinflammatory state contributes to coronary microvascular endothelial inflammation. Cytokine mediated inflammation prompts the endothelium to generate reactive oxygen species (ROS), resulting in endothelial dysfunction. ROS reduces nitric oxide bioavailability, cyclic guanosine monophosphate (cGMP) content, and protein kinase G activity (PKG) in adjacent cardiomyocytes. This finding is supported by the observation of lower PKG activity and elevated expression of nitrotyrosine, an oxidative stress marker, in the HFpEF myocardium compared to that of HFrEF. The decreased PKG activity promotes cardiomyocyte hypertrophy and increases resting tension due to hypophosphorylation of the protein titin, a protein normally responsible for passive cardiomyocyte tension. Both stiff cardiomyocytes and interstitial fibrosis ultimately contribute to high diastolic left ventricular stiffness and the development of HFpEF.
CKD is also associated with endothelial dysfunction and inflammation. High levels of fibroblast growth factor 23 (FGF23) present in CKD patients have been shown to cause endothelial dysfunction and induce myocardial remodeling. It is also postulated that FGF23 may contribute to HFpEF through vascular calcification and renal sodium handling. In a recent CRIC (Chronic Renal Insufficiency Cohort) study, elevated FGF23 levels were associated with increased risk of all HF subtypes. Furthermore, Vitamin D deficiency, hyperphosphatemia, and elevated levels of parathyroid hormone (PTH) have also been associated with ventricular hypertrophy and fibrosis. Impaired renal clearance leads to the retention of uremic toxins, which in turn promotes chronic inflammation driven by uremia-associated proinflammatory cytokines.
Therefore, through various mechanisms, CKD promotes a chronic proinflammatory state, which in turn contributes to the development of HFpEF through the mechanism described above, as summarized in Figure 2 .
Neurohormonal activation
HFpEF is also characterized by the activation of various neurohormonal pathways, particularly the renin-angiotensin-aldosterone system and the sympathetic nervous system, albeit to a lesser degree compared to HFrEF. A HF cohort study, comprising patients across different LVEF classes, investigated the extent of neurohormonal activation, as indicated by circulating biomarkers (plasma renin activity, aldosterone, catecholamines and NT-proBNP). The findings revealed that 67% of the HFpEF patients had elevated levels of at least 1 biomarker, and 10% of the HFpEF patients exhibited increased values of plasma renin activity, aldosterone, and norepinephrine, compared to 21% in HFrEF.
This neurohormonal activation leads to significant cardiovascular and renal effects. The mineralocorticoid receptor (MR) is a nuclear transcription factor expressed in various tissues, including kidney, heart, and vascular tissue. It plays a critical role in regulating fluid, electrolytes, blood pressure, and hemodynamic stability, and is implicated in metabolic, proinflammatory, and profibrotic pathways. Both CKD and HFpEF are associated with MR overactivation, leading to increased salt and water retention, inflammatory and fibrotic gene expression, ultimately resulting in increased myocardial stiffness, impaired LV relaxation, and glomerular and interstitial fibrosis in the kidneys.
The sympathetic nervous system also contributes to the development of HFpEF, particularly when accompanied by diastolic dysfunction. Notably, the structural changes observed in the myocardium of individuals with HFpEF resemble those associated with catecholamine-induced cardiomyopathies.
It remains inconclusive whether neurohormones drive the development of HFpEF or if HFpEF leads to increased neurohormone levels. Nonetheless, there is a bidirectional relationship between neurohormonal activation and HFpEF, and once 1 condition is established, a vicious cycle ensues.
Hemodynamic changes
In advanced HFpEF, the predominant hemodynamic features include elevated left- and right-sided filling pressures. This is the result of increased ventricular stiffness and diastolic dysfunction, a hallmark of HFpEF. Diastolic dysfunction is also prevalent in CKD patients and has been identified as an independent risk factor for CKD progression.
Right ventricular dysfunction in HFpEF is common and has been associated with lower eGFR. Increased right ventricular filling pressures lead to increased central venous pressure (CVP). This elevated CVP is transmitted to the renal veins, and as renal interstitial hydrostatic pressure increases, venous outflow and arterial inflow reduces, ultimately decreasing the glomerular filtration rate. This phenomenon has been proposed as part of a clinical entity named congestive nephropathy. This association between increased CVP and reduced GFR is significantly stronger in patients with relatively preserved cardiac output. Additionally, venous congestion may contribute to a vicious cycle involving hormonal activation, increased intra‐abdominal pressure, excessive renal tubular sodium reabsorption, and volume overload, ultimately leading to further right ventricular stress.
Increased left ventricular filling pressures lead to elevated pulmonary pressures, contributing to the symptoms of dyspnea and reduced exercise capacity. Another common feature of HFpEF contributing to exercise intolerance is chronotropic incompetence, which is thought to derive from impaired B-receptor sensitivity. Lower eGFR is also independently associated with chronotropic incompetence.
Another key hemodynamic feature of HFpEF is decreased systolic filling, resulting in inadequate stroke volume reserve. This ultimately results in a decreased cardiac output and consequently decreased renal blood flow.
In summary, HFpEF and CKD also exacerbate 1 another through hemodynamic mechanisms. HFpEF impairs renal perfusion and promotes venous congestion, further accelerating renal dysfunction. Conversely, CKD contributes to volume overload and cardiac structural and functional changes, including diastolic dysfunction, further aggravating HFpEF. This self-perpetuating cycle is related to the worse outcomes observed in these population.
Iron deficiency
Iron deficiency (ID) is highly prevalent in both CKD and HFpEF, contributing to poorer cardiovascular outcomes, reduced exercise capacity and tolerance, and diminished quality of life. Recent meta-analysis data indicate that ID is present in as many as 59% of patients with HFpEF. In a large CKD cohort, ID, regardless of cause, was associated with higher HF hospitalization risk.
The impact of ID extends beyond reduced oxygen delivery, as iron plays a crucial role in mitochondrial function and energy metabolism. Iron is also fundamental for the normal activity of ROS scavenging enzymes. Moreover, iron is required for proper cardiomyocyte contraction and relaxation and is highly important in high energy-demand cells, such as those of the heart and kidneys.
Patients with HF and CKD are both susceptible to ID through common pathways, including elevated hepcidin levels associated with systemic inflammation, reduced intestinal absorption due to mucosal edema, as well as malnutrition, and blood losses.
ID itself, through oxidative stress, mitochondrial damage, and endothelial dysfunction, also contributes to the development of HFpEF. Animal studies suggest that severe ID causes significant cardiac remodeling, with evidence of ventricular hypertrophy and fibrosis. In HFpEF patients, worse diastolic function has been reported in those with ID.
In CKD, anemia is often present due to ID and erythropoietin deficiency. In contrast to HF, the treatment of ID regardless of anemia has not been a primary focus in the management of CKD. In HFrEF, the correction of ID, independent of anemia, has proven beneficial and is recommended. The role of iron therapy has been less clear in the HFpEF population. However, the recent randomized, double-blind, placebo-controlled FAIR-HFpEF trial showed an improvement in exercise capacity with ferric carboxymaltose, as assessed by the 6-minute walking test distance. The trial revealed an average increase of 49 meters within 24 weeks, but no significant effect on quality-of-life assessments or NYHA functional class, indicating the need for further research. Importantly, there were no significant changes in laboratory markers of kidney function. The safety of intravenous iron use in CKD patients is further supported by the FIND-CKD trial.
Common risk factors
As described above, multiple pathways contribute to the interplay between cardiac and renal dysfunction. An additional contributing factor is the presence of common underlying risk factors such as hypertension, diabetes, and obesity. These comorbidities contribute to systemic inflammation, endothelial dysfunction, and microvascular disease, all of which are central to the development and progression of both HFpEF and CKD. In contrast to HFrEF, comorbidities play a more dominant role in the pathophysiology of HFpEF.
Hypertension is a major risk factor for CKD and the most important identified cause of HFpEF, with a prevalence of 60% to 89% in the HFpEF population. Hypertension leads to elevated left ventricular afterload, resulting in LV hypertrophy and diastolic dysfunction, all key features of HFpEF. Simultaneously, hypertension exacerbates CKD through glomerular hyperfiltration and subsequent nephron loss. ,
Diabetes leads to both HFpEF and CKD through mechanisms including hyperglycemia-induced endothelial dysfunction, increased oxidative stress, and inflammation. These pathophysiological processes contribute to myocardial stiffening and fibrosis in HFpEF, as well as glomerulosclerosis in CKD. The reported prevalence of DM in individuals with HFpEF ranges from 28% to over 40%. Furthermore, CKD and DM frequently co-occur in patients with HFpEF, and the presence of both conditions significantly increases the risk of adverse cardiovascular outcomes.
Obesity is another strong risk factor for HFpEF, with up to 80% of patients being overweight or obese. Clinical obesity can lead to severe organ dysfunction, including renal failure, with obesity-related glomerulopathy being a well-recognized complication. In fact, renal function tests should always be performed in the initial assessment of patients with increased adiposity.
Increased adiposity contributes to various pathways that promote inflammation, oxidative stress, and dysfunction in the heart and kidneys. Emerging evidence suggests that adipocytes may secrete aldosterone or aldosterone-secreting factors, leading to increased aldosterone levels in obesity and metabolic syndrome. In fact, obesity and other major risk factors of HFpEF and CKD, such as insulin resistance, dyslipidemia, diabetes, and metabolic syndrome, can all lead to MR overactivation, further exacerbating the pathophysiology of HFpEF and CKD.
Dyslipidemia promotes the development of atherosclerosis, which can impair coronary microcirculation and renal perfusion, thereby contributing to ischemic injury in both the myocardium and kidneys.
Atrial fibrillation is another highly prevalent comorbidity of HFpEF and CKD. AF is more likely to precede the development of HFpEF but can also follow, as the relationship between both is bidirectional. AF contributes to atrial and ventricular fibrosis, impairing diastolic filling. It is thought to worsen or drive HF through tachycardia-induced cardiomyopathy, loss of atrial systole, functional mitral regurgitation, and the activation of the RAS system. Conversely, HFpEF promotes AF through atrial remodeling , driven primarily by systemic inflammation pathways . Most functional and hemodynamic measurements, such as cardiac output reserve, filling pressures, LA stiffness and reservoir function, worsen across FA stages.
This reciprocal relationship also extends to CKD, with inflammation again playing a key role, as numerous inflammatory mediators have been implicated in the pathogenesis of CKD-induced AF. Large cohorts have found that CKD and AF patients are at higher risk of ischemic stroke, major bleeding, and all-cause mortality . CKD in patients with AF also increases the risk of developing HF. Furthermore, incident HF in AF patients with CKD is associated with a faster decline in kidney function and a higher risk of stroke and other cardiovascular complications.
Further highlighting this interrelationship are the findings of a pooled analysis from trials in HFpEF, overweight, CKD and T2D populations, in which finerenone was shown to decrease the risk of new onset AF .
Importantly, AF, CKD, and HFpEF are independently associated with an increased risk of cognitive impairment, even after accounting for stroke. This is likely due to shared vascular risk factors, neuroinflammation, direct impacts on cerebral blood flow, and an elevated risk of silent cerebrovascular damage. , These findings highlight the importance of an integrated, evidence-based strategy for managing comorbid conditions.
In summary, the relationship between HFpEF and CKD may be both bidirectional, or stem from shared underlying comorbidities. Managing these comorbidities effectively is essential for breaking this cycle and improving outcomes in this patient population.
Diagnostic Challenges in Patients With HFpEF and CKD
The complex interplay between HFpEF and CKD also poses significant challenges in the accurate diagnosis and assessment of both conditions. This is due to the significant overlap in clinical symptoms, the nonspecific elevation of heart failure biomarkers, and the difficulties in accurately assessing renal function.
Therefore, this intricate relationship also requires a multidisciplinary approach to diagnosis. The development of validated diagnostic scoring systems and new biomarkers could facilitate the early detection of HFpEF in CKD patients. For instance, the 2 diagnostic scoring systems for HFpEF, the H2FPEF and HFA-PEFF scores, may prove helpful in this context, however they have not been specifically validated for use in patients with CKD. Echocardiographic criteria are essential for both scores, and particularly when diagnosing HFpEF in CKD patients, the echocardiography should assess the degree of diastolic dysfunction.
Clinical presentation
The clinical presentation of HFpEF includes dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, edema and jugular venous distension. Many of these symptoms, particularly fatigue, dyspnea, and edema, overlap with those observed in CKD, making it difficult to distinguish between the 2 conditions based solely on clinical presentation. Additionally, patients with concomitant HFpEF and CKD usually present with worse symptoms and exercise tolerance, also reflected in worse NYHA functional class.
The overlap between HFpEF and CKD can lead to delayed diagnosis, highlighting the need for proactive HF screening in CKD patients. This underdiagnosis of HF in CKD populations was evident in a recent prospective cohort study, where 15.3% of CKD patients were diagnosed with symptomatic HF, yet only 8.8% had an HF diagnosis at baseline.
CKD assessment in HFpEF patients
CKD is defined as reduced kidney function for at least 3 months, evidenced by an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² or other markers of kidney damage, such as albuminuria (albumin-to-creatinine ratio ≥30 mg/g). In addition to the GFR category, the cause and albuminuria category are essential to better stratify the risk and classify CKD. Another important measure is the albumin-to-creatinine ratio (ACR), whose increase is associated with the risk of many complications of CKD, including HF.
In patients with HFpEF, muscle mass loss or volume expansion can lead to a falsely reduced serum creatinine, making it challenging to accurately assess CKD in this patient population, as the glomerular filtration rate may be overestimated. Therefore, in the setting of HFpEF to better evaluate the true extent of renal impairment other markers should be considered, such as albuminuria, evidence of secondary hyperparathyroidism, and creatinine levels response to diuresis. Additionally, the CKD-EPI formula should be the preferred creatinine-based equation for clinical risk stratification in HFpEF patients, as it has demonstrated superior performance compared to the MDRD equation.
Growing evidence also suggests that in HFpEF, serum cystatin C is a more accurate marker for estimating GFR, providing additional clinical and prognostic information compared to creatinine. In a prospective study of HFpEF patients enrolled in the Johns Hopkins Program, when using cystatin C instead of creatinine to estimate GFR, 39% of patients were reclassified to a higher stage of CKD. This trend was also observed in a post hoc analysis of the SUMMIT trial, where 61% of patients had CKD when using cystatin C, compared to only 46% when using creatinine.
Even with cystatin C, there are substantial individual-level discrepancies between measured and estimated glomerular filtration rate. Accordingly, for routine GFR evaluation, current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend using combined creatinine and cystatin C (eGFRcr-cys) or cystatin C alone (eGFRcys) to estimate the GFR. However, if GFR is being used for treatment decisions, measured GFR should be the preferred method.
Biomarkers
Renal dysfunction can also impact the interpretation of heart failure biomarkers. Natriuretic peptide levels are typically elevated in CKD, reducing their specificity for diagnosing HFpEF. Therefore, in this context, the interpretation of NT-proBNP levels should be cautious, adjusting to higher cut point values in accordance with eGFR.
Even though no biomarker has proven superior to NT- proBNP, newer biomarkers may provide additional diagnostic and prognostic value in HFpEF patients with CKD. For example, carbohydrate antigen 125 (CA125) was significantly associated with worse functional capacity in HFpEF, irrespective of eGFR, outperforming NT-proBNP. CA125 could be a useful biomarker for estimating effort intolerance in HFpEF patients with CKD. Suppression of tumorigenicity2 (sST2) is also less affected by declining renal function. The combined model of sST2 and NT-proBNP was superior to the model of sST2 or NT-proBNP alone, for accurately diagnosing HF in patients with CKD. The measurement of serum osteoprotegerin (OPG) levels may also aid in the diagnosis of HFpEF in CKD patients, as osteoprotegerin (OPG) serum levels are associated with the risk of LV diastolic dysfunction in predialysis CKD.
Treatment of HFpEF in patients with CKD
The management of HFpEF requires a multifaceted approach that addresses the underlying comorbidities and implements nonpharmacological strategies, with a focus on weight loss and increased physical activity, as well as pharmacological strategies with initiation of GDMT (Guideline-Directed Medical Therapy).
Initially, the GDMT that demonstrated success in HFrEF did not prove as beneficial in HFpEF, with disappointing clinical trial results, particularly with neurohormonal targeting therapies failing to show a reduction in mortality outcomes. This divergence highlighted the distinct pathophysiology of HFpEF, but also led to fewer optimal treatment options available for this population. Nonetheless, recent clinical trials have demonstrated benefits of pharmacological therapies in patients with HFpEF, particularly the use of SGLT2i (Sodium-Glucose Cotransporter-2 Inhibitors), and Finerenone. Additionally, new therapies, such as GLP1 RA (Glucagon-Like Peptide1 Receptor Agonists), show promising results (Section 7).
Adopting lifestyle modifications is essential for improving outcomes and is a cornerstone in the management of HFpEF, CKD, and their associated comorbidities. These changes should particularly focus on optimizing nutrition, increasing physical activity, managing weight, and promoting smoking cessation.
Managing comorbidities is crucial. For instance, elevated blood pressure (BP) is related to worse clinical outcomes in HFpEF and CKD. Recent studies suggest that an intensive BP control regime is more effective than the standard regime in reducing cardiovascular outcomes. Accordingly, current guidelines recommend targeting systolic BP to 120-129 mmHg in CKD patients. RASi (renin-angiotensin system inhibitors) are the preferred drug class for managing hypertension in patients with CKD. SGLT2is should be initiated in all patients with symptomatic HFpEF, offering the added benefit of modest BP reduction. In the HFpEF population, if BP targets are not achieved with SGLT2i, ARBs or mineralocorticoid receptor antagonists (MRAs) can also be considered. Additionally, sacubitril-valsartan, although not yet guideline endorsed for hypertension management, effectively lowers BP in HFpEF patients. Emerging HFpEF therapies, such as non steroidal MRAs and GLP-1 RA also present BP lowering effects.
CKD is also a major comorbidity of HFpEF and should be treated as such per KDIGO guidelines. Furthermore, the presence of CKD in patients with HFpEF warrants special considerations and precautions, but also highlights the importance of implementing therapies with both positive heart failure and kidney function outcomes. These renal considerations and benefits are outlined below, alongside the drug classes that can be considered in the treatment of HFpEF ( Table 1 and Table 2 ).
Table 1
Summary of cardiovascular and renal outcomes of major RCTs in HFpEF
| Trial | Class (Drug) | Primary cardiovascular outcome | Renal outcomes | LVEF inclusion criteria/ Mean baseline LVEF | eGFR inclusion criteria/ Mean baseline eGFR |
|---|---|---|---|---|---|
| EMPEROR-Preserved | SGLT2i (Empagliflozin) | CV death or HF hospitalization: HR 0.79; 95% CI 0.69 to 0.90; p < 0.001 | Slowed eGFR decline; Kidney composite outcome (with CKD: HR 0.97; 95% CI 0.71 to 1.34; without CKD: HR 0.92; 95% CI 0.58 to 1.48) | >40%/ ∼54% | ≥20 ml/min/1.73 m²/ ∼61 |
| DELIVER | SGLT2i (Dapagliflozin) | CV death or worsening HF: HR 0.82; 95% CI 0.73 to 0.92; p < 0.001 | Slowed eGFR decline; Kidney composite outcome : HR 1.08; 95% CI 0.79 to 1.49 | >40%/ ∼54% | ≥25 ml/min/1.73 m²/ ∼61 |
| TOPCAT | MRA (Spironolactone) | CV death, aborted cardiac arrest, or HF hospitalization: HR 0.89; 95% CI 0.77 to 1.04; p = 0.14 | Higher rates of WRF and hyperkalemia | ≥45%/ ∼56% | ≥30 ml/min/1.73 m²/ ∼65 |
| FINEARTS-HF | Nonsteroidal MRA (Finerenone) | Total worsening HF events and CV death: RR 0.84; 95% CI 0.74 to 0.95; p = 0.007 | Higher rates of hyperkalemia Kidney composite outcome : HR: 1.33; 95% CI 0.94 to 1.89 | ≥40%/ ∼53 | ≥25 ml/min/1.73 m²/ ∼62 |
| PARAGON HF | ARNI (Sacubitril/ Valsartan) | CV death and total HF hospitalizations: RR 0.87; 95% CI 0.75 to 1.01; p = 0.06 | Kidney composite outcome : HR 0.50; 95% CI, 0.33 to 0.77; p = 0.001 | ≥45%/ ∼58% | ≥30 ml/min/1.73 m²/ ∼63 |
| CHARM-Preserved | ARB (Candesartan) | CV death and HF hospitalization: HR 0.86; 95% CI 0.74 to 1.00 | Higher rates of WRF versus placebo | >40%/ ∼54% | NR |
| I-PRESERVE | ARB (Irbesartan) | All-cause mortality or CV hospitalization: HR 0.95; 95% CI 0.86 to 1.05; p = 0.35 | Higher rates of WRF versus placebo | ≥45%/ ∼59% | NR/ ∼73 |
| J-DHF | β-blocker (Carvedilol) | CV death and HF hospitalization: HR 0.902; 95% CI 0.546 to 1.488; p = 0.6854 | NR | ≥40%/ ∼63% | ≥30 ml/min/1.73 m²/ ∼58 |
| STEP-HFpEF Program | GLP1 RA (Semaglutide) | KCCQ-CSS: + 7.5 points; 95% CI 5.3 to 9.8; p < 0·0001 | NR | ≥45%/ ∼57% | NR/∼69 |
| SUMMIT | GLP1/GIP RA (Tirzepatide) | CV death or worsening HF: HR 0.62; 95% CI 0.41 to 0.95; p = 0.026 | eGFR at 52 weeks +1.9, 95% CI: 0.2 to 3.7; p = 0.028 with eGFR-cr vs +2.9, 95% CI: 0.9 to 4.9; p = 0.004 with eGFR-cys | ≥50%/∼61% | ≥15 ml/min/1.73 m²/ NR |
Table 2
Comparative summary of drug class recommendations in HFpEF and in CKD according to current guidelines
| HFpEF | CKD | ||
|---|---|---|---|
| Drug class | 2023 ACC Expert Consensus | 2022 AHA/ACC/HFSA | KDIGO 2024 |
| SGLT2i | Class 1 | Class 2a | Class 1a for CKD patients with HF or T2D or albuminuria ≥200 mg/g |
| Steroidal MRAs | Class 2b for women (all EFs) and for men EF <55%-60% | May be used for treatment of heart failure, hyperaldosteronism, or refractory hypertension | |
| Nonsteroidal MRAs | Not yet guideline-endorsed for HFpEF | Class 2a for T2D and albuminuria ≥30 mg/g despite RASi optimization | |
| ARNI | Class 2b for women (all EFs) and for men EF <55%-60% | Not mentioned | |
| RASi | Class 2b for ARBs when ARNI not tolerated; ACEi not recommend | Class 1b for CKD and severe albuminuria (A3) or CKD and diabetes and albuminuria (≥A2) | |
| BBs | Not recommended for HFpEF unless other clear indication (e.g. AF, angina). | Not mentioned | |
| GLP-1 RA | Not yet guideline-endorsed for HFpEF | Class 1b for T2D and CKD for individuals who have not achieved glycemic targets despite use of metformin and SGLT2i | |
ACEi = angiotensin-converting enzyme inhibithor; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; AF = atrial fibrillation; BB = beta-blocker; CKD = chronic kidney disease; EF = ejection fraction; GLP1 RA = glucagon-like peptide-1 receptor agonist; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; MRAs = mineralocorticoid receptor antagonists; RASi = renin angiotensin system inhibitor; SGLT2i = sodium-glucose co-transporter-2 inhibitor; T2D = type 2 diabetes.
Challenges in treatment
The coexistence of HFpEF and CKD presents significant treatment challenges. These can be attributed to the higher comorbidity burden in this patient population, the risk of further renal impairment, and the lack of evidence or safety concerns regarding pharmacological therapies in the CKD population, largely due to the underrepresentation of CKD patients in clinical trials.
Additionally, the pathophysiology of these 2 conditions and drug interactions makes volume and potassium management particularly challenging.
Volume management
Volume management is crucial in the symptomatic management of HFpEF, and loop diuretics are the recommended agents for this purpose. However, CKD patients are prone to fluid retention and diuretic resistance, and diuretic use can also aggravate renal function. Therefore, loop diuretics should be used at the lowest effective dose, and if the response is suboptimal, thiazide diuretics may be used in combination.
SGLT2i, as a nephroprotective therapy with diuretic action, can be a preferred option in this cardiorenal population. A post hoc analysis of the EMPEROR-Preserved trial showed that empagliflozin was associated with a decreased need for conventional diuretic use, and its safety and efficacy profile was unaffected by baseline diuretic therapy. , A small study in a T2D and HF population (including HFpEF patients) evaluated the association of empagliflozin with loop diuretics and demonstrated an important synergetic effect, with more effective diuresis with this combination, while maintaining a safe kidney and electrolyte profile.
As loop diuretics are often less effective with declining renal function, and dose increases can worsen renal function and cause electrolyte imbalances, recent trials have evaluated the efficacy and safety of alternative diuretic strategies.
The ADVOR trial evaluated the addition of acetazolamide to standard loop diuretics in patients with acute decompensated heart failure (ADHF), including patients with an eGFR >20 ml/min/1.73m2. Acetazolamide was associated with more successful decongestion, particularly in patients with a lower eGFR. However, the acetazolamide arm, had a higher incidence of worsening renal function, though this did not lead to adverse clinical outcomes and had normalized within 3 months of discharge. It is important to note that patients receiving SGLT2i were excluded from the ADVOR trial.
An open-label, parallel-group randomized trial demonstrated that in patients with advanced CKD, the addition of tolvaptan, compared to increasing the dose of furosemide, achieved a greater increase in urine output and was less likely to worsen renal function. Most of the included patients had HFpEF, and although limited by a small sample size ( n = 33), other studies in HF populations with CKD have reported similar findings.
Potassium management
Elevated serum potassium levels in HF patients constitute a risk factor for cardiovascular complications and a major factor for not initiating or discontinuing RASi and MRAs. Additionally, potassium regulation is highly dependent on renal function. Consequently, ensuring proper potassium balance is a critical challenge for individuals with HFpEF and CKD.
Most information on potassium imbalances comes from randomized clinical trials in HFrEF, leaving a gap in real-world data on dyskalemia and its quantification in HFpEF. The analysis from the Swedish Heart Failure Registry on dyskalemia across the HF spectrum revealed that dyskalemia is even more relevant in HFpEF, with the highest risk of moderate or severe hyperkalemia found in HFpEF and HFmrEF, and the highest risk of hypokalemia also observed in HFpEF. Furthermore, advanced CKD patients were at higher risk for both hyper- and hypokalemia. Additionally, the occurrence of dyskalemia was associated with elevated mortality risk but not with HF hospitalization risk.
The TOPCAT trial, which assessed the use of spironolactone (MRAs) in HFpEF, reported lower rates of dyskalemia compared to the Swedish registry, with 11,4% versus 13,9% for hyperkalemia, and 17,5% versus 25,6% for hypokalemia. , Nonetheless, it is clear that dyskalemia is a relevant concern in the HFpEF population, and further research is necessary to better understand and manage it in this population.
Treatment with new potassium binders, patiromer or sodium zirconium cyclosilicate (SZC), can be an effective strategy for hyperkalemia management in the cardiorenal population. , Although there is limited evidence for their specific use in HFpEF, they may help improve outcomes by facilitating continuation of RASi or MRAs.
SGLT2 inhibitors
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed for the treatment of type 2 diabetes (T2D), but the significant improvement in renal and cardiovascular outcomes observed in those trials expanded their use to HF and CKD populations. They were first approved for HFrEF and later demonstrated benefits in HF regardless of EF. The benefits in HFpEF were most striking in 2 RCTs that studied the effect of SGLT2i in HF patients with a LVEF >40%, the EMPEROR- Preserved trial and the DELIVER trial.
In the EMPEROR-Preserved trial, empagliflozin, compared to placebo, demonstrated a 21% lower relative risk in the primary composite outcome of cardiovascular death or hospitalization for heart failure. In the DELIVER trial, dapagliflozin led to an 18% reduction in the primary composite outcome of worsening heart failure or cardiovascular death, and resulted in a lower symptom burden compared to placebo. The cardiovascular benefit was consistent across the full range of ejection fraction, with similar results in the LVEF >60% and <60% subgroups of the DELIVER trial. This favorable effect was also observed in the EMPEROR-Preserved trial, with posterior analysis suggesting only a more attenuated effect in patients with LVEF ≥65%. ,
Importantly, in both trials, the primary composite outcome reduction was mainly due to a decrease in hospitalizations for HF, rather than a statistically significant reduction in cardiovascular deaths. , In fact, the impact of SGLT2i on cardiovascular mortality has been inconsistent across different clinical trials. Pooled analysis from the EMPEROR-preserved and DELIVER trial, and meta-analyses including other trials on SGLT2i in HFpEF have failed to demonstrate that SGLT2i significantly reduce cardiovascular death, though some do show a trend towards benefit. ,
This drug class has also demonstrated a nephroprotective effect, with many studies investigating its impact on CKD patients. The EMPA-Kidney trial and DAPA-CKD trial, 2 major RCTs focused on CKD populations (with an eGFR of at least 20 ml/min/1.73 m²), demonstrated that SGLT2i significantly reduced the risk of kidney disease progression, independent of diabetes status. , A meta-analysis, comprising both these trials and 11 more, revealed a 37% reduction in the risk of kidney disease progression and a 23% reduction in the risk of acute kidney injury.
Considering the established cardiovascular benefits of SGLT2i, current guidelines recommend their use in all HFpEF patients, lacking contraindications (e.g., lactation, patients on dialysis). Additionally, for HFpEF patients with CKD, SGLT2i represent a powerful therapeutic option that can benefit both conditions. However, cautionary use is advised when the eGFR is below 20 ml/min/1.73 m² (for empagliflozin) or 25 ml/min/1.73 m² (for dapagliflozin).
Mineralocorticoid receptor antagonists
As discussed above, MR overactivation is a key factor in the pathogenesis of both HFpEF and CKD. Furthermore, MR antagonists have demonstrated clinical benefits in HFrEF. As a result, MRAs also seemed promising in HFpEF, and while initial trials yielded conflicting findings, more recent trials in HFpEF have shown positive results. This change can be attributed to the development of nonsteroidal MRAs, a class with greater receptor selectivity, more potent antifibrotic and anti-inflammatory properties, and reduced hormone-related side effects.
The benefit of spironolactone, a steroidal MRA, in HFpEF was evaluated in the TOPCAT trial, which enrolled 3445 patients with symptomatic HF with LVEF ≥45%. The trial failed to demonstrate a statistically significant reduction in the primary composite outcome, demonstrating however a significant reduction in hospitalizations for HF. Importantly, post hoc analyses revealed regional differences, with a significant decrease in the primary composite outcome in the Americas group, but not in the Russia/Georgia group, a notably younger and less comorbid group. These differences can also be attributed to variations in the enrolment process and adherence to protocol. In the Russia/Georgia group, most participants were enrolled based on HF hospitalization criteria and not natriuretic peptide criteria, and 30% had undetectable active spironolactone metabolites, compared to only 3% in the Americas. Other post hoc analysis suggest that spironolactone provides higher benefits in certain patient subgroups, such as those with higher BMI, lower LVEF (<55%-60%), and in female patients, regardless of LVEF. ,
The TOPCAT trial included patients with an eGFR above 30 ml/min/1.73 m2, and spironolactone efficacy was consistent across all eGFR groups, with no significant difference in renal adverse effects such as hospitalizations, deaths, or dialysis compared to placebo. However, due to higher rates of worsening renal function and hyperkalemia, close monitoring of creatinine and potassium levels is recommended, particularly in patients with an eGFR below 45 ml/min/1.73 m2.
With the development of nonsteroidal MRAs, particularly finerenone, a new hope has emerged in the management of cardio-renal syndromes. In 2 large RCTs involving patients with CKD and T2D, the FIDELIO-DKD and FIGARO-DKD trials, finerenone reduced the risk of kidney disease progression and led to a significant reduction in cardiovascular events, including CV death, hospitalizations for HF, and the risk of new-onset HF. In both trials around 7.7% to 7.8% of patients had baseline HF and symptomatic HFrEF patients were excluded, suggesting some representation of the HFpEF population in these trials, though the exact percentage is not reported. ,
The effect of finerenone in HFpEF was evaluated in the FINEARTS-HF trial, an international, randomized, double-blind, placebo-controlled trial, which enrolled 6001 patients with a LVEF ≥40%. Finerenone significantly reduced the primary composite outcome of worsening HF events and CV deaths by 16% (RR, 0.84; 95% CI, 0.74 to 0.95; p = 0.007). This benefit was consistent across the LVEF ≥40% spectrum and regardless of SGLT2i use. Additionally, finerenone led to an improved patient-reported health status (measured by the KCCQ total symptom score) but not to a NYHA functional class improvement. The FINEARTS-HF trial included patients with an eGFR ≥25 ml/min/1.73 m2 and unlike in the FIDELIO-DKD and FIGARO-DKD trials, finerenone did not lower the risk of secondary kidney composite outcome. Furthermore, elevated creatinine levels and hyperkalemia were more frequent with finerenone compared to placebo. However, the incidence of serious adverse events was similar between the 2 groups.
With these new findings, nonsteroidal MRAs can represent alongside SGLT2i the new frontier in the management of HFpEF and comorbid CKD. This class combination has proven beneficial in CKD patients with T2D, in which finerenone and empagliflozin together achieved a greater reduction in the urinary albumin-to-creatinine ratio (UACR) than either treatment alone, as shown in the CONFIDENCE trial. Other class combinations are being studied in clinical trials, particularly the use of balcinrenone in addition to dapagliflozin. The MIRACLE trial, which included 133 high-risk stage 3 CKD patients, evaluated the effect of this combination versus placebo plus dapagliflozin, but failed to show a significant reduction in urinary albumin-to-creatinine ratio (UACR) or NT-proBNP levels. However, due to a smaller sample size and earlier termination than predicted, these findings are harder to interpret. Hopefully, the forthcoming BALANCED-HF (NCT06307652) trial, evaluating the effect of balcinrenone/dapagliflozin in HF patients (across the full spectrum of LVEF) with CKD (eGFR 20-60 ml/min/1.73 m 2), will provide more elucidating results.
Further evidence on the effectiveness of steroidal MRAs in HFpEF is also warranted, and the SPIRIT-HF trial (NCT04727073) and ongoing SPIRRIT-HFpEF trial (NCT02901184) are expected to address this knowledge gap. Additionally, the REDEFINE-HF trial (NCT06008197) will assess the effect of finerenone in the acute setting of HFpEF.
Currently, MRAs have a class 2b recommendation for specific subsets of patients with HFpEF, but the positive results from the FINEARTS trials are expected to change this recommendation. In summary, recent findings have identified MRAs, particularly nonsteroidal ones, as a promising therapeutic option for HFpEF and CKD. Additionally, future evidence from upcoming trials is expected to better guide therapeutic decisions in this patient population.
Angiotensin receptor-neprilysin inhibitors
Angiotensin receptor-neprilysin inhibitors (ARNIs) consist of a combination of sacubitril and valsartan, a neprilysin inhibitor and an angiotensin receptor blocker (ARB), respectively. Sacubitril inhibits the clearance of natriuretic peptides, thereby promoting their vasodilatory, diuretic, and natriuretic effects. This combination yielded additional benefits in the treatment of HFrEF, and was thereafter also studied in HFpEF, most notably in the PARAGON HF trial.
The PARAGON HF trial enrolled 4822 patients with LVEF >45%, comparing the effects of sacubitril/valsartan and valsartan. The trial failed to demonstrate a significant reduction in the primary outcome of HF hospitalizations and CV death, but did show a modest, though not statistically significant, decrease in HF hospitalizations. Exploratory secondary outcome analysis suggested an improvement in the quality of life with sacubitril/valsartan. Further analysis detected heterogeneity in treatment effect in women and in patients with LVEF <57%, suggesting a higher benefit of ARNIs in these populations.
Regarding renal outcomes in the PARAGON HF trial, in which patients with an eGFR <30 ml/min/1.73m2 were excluded, ARNIs demonstrated a more pronounced nephroprotective effect compared to valsartan alone. This was evident in significantly reduced risk of renal events and a slower rate of decline in eGFR. This effect of sacubitril/valsartan in kidney outcomes was consistent across baseline eGFR. Interestingly, a recent subanalysis of the PARAGON HF trial found that the cardiovascular benefit of ARNIs was greater in patients with lower eGFR, with treatment effect being most pronounced in those with an eGFR ≤45 ml/min/1.73 m 2.
Trials in HF populations have supported the renal benefits of ARNIs. However, their effect on CKD is less clear. For instance, the HARP-III trial, which assessed sacubitril/valsartan versus irbesartan in 414 patients with CKD (eGFR 20-60 ml/min/1.73 m2) found no significant difference in the primary outcome of measured GFR at 12 months between the treatment groups.
More recently, the PARAGLIDE-HF trial evaluated the effect of sacubitril/valsartan in comparison with valsartan in patients with LVEF >40% after a worsening heart failure event. The primary endpoint of reduction in plasma NT-proBNP levels was achieved, and clinical secondary outcomes trended towards favoring sacubitril/valsartan but were not statistically significant. However, the trial was not adequately powered to examine clinical outcomes. Patients with eGFR > 20 ml/min/1.73 m2 were included, and sacubitril/valsartan led to a decrease in worsening renal function. Similar to previous trials, a greater treatment effect was observed in patients with LVEF <60%.
Pooled analysis from the PARAGLIDE-HF and PARAGON HF trials have demonstrated that sacubitril/valsartan significantly reduced the composite outcome of HF hospitalizations and CV death. In terms of side effects, ARNIs were associated with a higher risk of hypotension but no increased risk of hyperkalemia. ,
Given the positive cardiovascular and renal benefits of ARNIs, they can be considered in the management of HFpEF in patients with CKD. However, more robust evidence on the effects of ARNIs across the full range of EF and their renoprotective potential is needed.
Renin-angiotensin system inhibitors
As reviewed above, albeit to a lesser extent than in HFrEF, the renin-angiotensin-aldosterone system is also activated and involved in the pathophysiology of HFpEF. Renin-angiotensin system (RAS) inhibitors have been effective in improving mortality and morbidity outcomes in HFpEF and in managing major comorbidities of HFpEF, such as hypertension, diabetes, and CKD, due to their renoprotective and cardioprotective properties. Therefore, RAS inhibitors were expected to benefit HFpEF patients as well. However, clinical trials have demonstrated either no improvement in outcomes or only modest benefits of RAS inhibitors in HFpEF. ,,
Angiotensin converting enzyme (ACE) inhibitors, 1 of the 2 classes of RAS inhibitors, are not recommended for the management of HFpEF since they failed to demonstrate clinical benefits in the only major RCT with ACE inhibitors in HFpEF, the PEP-CHF trial with perindopril. The effect of angiotensin II receptor blockers (ARBs), the other class of RAS inhibitors, in HFpEF patients has been studied in 2 large RCTs, the CHARM-preserved trial with candesartan and the I-Preserved trial with irbesartan, yielding conflicting findings. In the CHARM-preserved trial, the primary composite outcome (HF hospitalization and CV death) was only of borderline significance, with no impact on cardiovascular death, but a moderate reduction in heart failure hospitalizations. In the I-Preserved trial, no benefit was achieved, either in the primary outcome (death and CV hospitalizations), its individual components, or in secondary outcomes. The disappointing and discordant results from these RCTs have been partly attributed to high dropout rates and frequent concomitant use of open-label RAS inhibitors.
Meta analysis of RCTs of RAS inhibitors in HFpEF have also found little to no effect of both ACE inhibitors and ARBs on the outcomes of cardiovascular mortality, all‐cause mortality, and heart failure hospitalization. Only data from observational studies indicates a potential benefit of ACE inhibitors and ARBs in reducing all-cause mortality in HFpEF patients. ,
RAS inhibitors have proven renoprotective benefits, reducing the progression of CKD and the incidence of cardiovascular events in CKD patients. However, specific data on the benefits of RAS inhibitors in CKD and HFpEF patients is more limited. In both the CHARM-preserved and I-Preserved trials, the use of candesartan and irbesartan, respectively, led to higher rates of worsening renal failure (WRF) compared to placebo. Furthermore, this WRF was associated with worse clinical outcomes in HFpEF patients. , A meta-analysis of 3 retrospective cohort studies found that RAS inhibitors significantly reduced all-cause mortality and all-cause hospitalization in patients with CKD and HFpEF. The same beneficial effect was not observed for hospitalization due to heart failure. posthoc analysis of the TOPCAT trial also supports these findings, indicating that the use of RAS inhibitors in patients with HFpEF and CKD significantly reduces the risk of cardiovascular events and all-cause mortality.
Currently, there are no specific recommendations for the use of RAS inhibitors in patients with both HFpEF and CKD in the KDIGO guidelines and the 2023 ACC Expert Consensus. The latter highlights that ARBs may be considered in the management of HFpEF when ARNIs are not an option due to cost or intolerance, as ARNIs are more effective than ARBs in HFpEF. In CKD management, however, ARNIs do not have an established role, and RAS inhibitors are the recommended class. Therefore, further insights into the benefits of RAS inhibitors and their comparative efficacy with ARNIs are needed to better guide the management of concomitant CKD and HFpEF.
Beta-blockers
Beta-blockers (BBs) are one of the pillars in the management of HFrEF, with robust evidence demonstrating significant reductions in mortality outcomes. However, their role in HFpEF remains unclear, even controversial, and is not supported by current guidelines. Despite this, BBs continue to be widely prescribed in HFpEF patients, probably due to their role in managing common cardiovascular comorbidities such as hypertension, coronary artery disease (CAD), and atrial fibrillation (AF).
The evidence base for BB use in HFpEF is limited and primarily comes from observational studies, as only few and older RCTs assessed BBs in HFpEF. In the SENIORS trial, nebivolol reduced the composite outcome of all-cause mortality or cardiovascular hospitalization in elderly patients with heart failure, but only a small proportion (15%) had an LVEF >50%, and post hoc analyses found no benefit in this subgroup. Similarly, the J-DHF trial, which evaluated carvedilol in patients with LVEF >40%, showed neutral effects on cardiovascular death and heart failure hospitalization.
Meta-analyses on BBs effect in HFpEF have yielded conflicting findings. Pooled analysis from observational cohort studies, suggest that BBs significantly reduce all-cause mortality in HFpEF patients, but demonstrate no effect on hospitalizations for HF. Some studies report a neutral effect on both mortality and hospitalization outcomes, while others even suggest an adverse effect, with increased HF hospitalization risk. In the U.S. PINNACLE Registry, BB use was associated with higher HF hospitalization rates in older patients with HFpEF, while providing no survival benefit. These findings align with a post hoc analysis of the TOPCAT trial, which also reported increased HF hospitalizations without a mortality advantage in HFpEF patients receiving BBs. Conversely, DELIVER post hoc analysis and data from the Swedish HF registry do not show an association between BBs and increased worsening HF risk, or cardiovascular death. , Recent pooled analyses from major HFpEF trials (I-PRESERVE, TOPCAT, PARAGON HF, DELIVER) also showed no difference in hospitalization risk between BB users and nonusers. Adjusted analyses even demonstrated a reduction in the composite outcome of cardiovascular death or HF hospitalization, independent of LVEF, prior myocardial infarction, or hypertension.
Importantly, a growing body of evidence raises concerns about the safety and tolerability of BBs in HFpEF, as chronotropic incompetence, commonly present in HFpEF, can be exacerbated by BBs, potentially worsening exercise intolerance. The PRESERVE-HR trial demonstrated that BB withdrawal in HFpEF patients with chronotropic incompetence improved peak oxygen consumption and exercise heart rate. These findings highlighted the need for cautionary use of BBs, particularly in HFpEF patients without compelling indications for BB therapy. In contrast, a meta-analysis of RCTs found no significant effect of BBs on NYHA class, exercise capacity, or BNP levels in HFpEF patients, though substantial heterogeneity existed across studies. Notably, in meta-regression analysis, improvements in NYHA class and exercise capacity were more frequently seen in patients with CAD or AF, suggesting that in these subgroups, the improved left ventricular diastolic filling may offset BBs negative chronotropic effects.
In patients with concomitant CKD and HFpEF, the evidence supporting BB use is even more limited. Unlike in HFrEF, where BBs confer survival benefits in patients with CKD, studies in HFpEF have failed to show similar advantages. Observational data from the Swedish Heart Failure Registry revealed no association between BB use and improved cardiovascular or renal outcomes in patients with advanced CKD and HFpEF. Similarly, cluster analyses of HFpEF patients found no benefit of BBs in decreasing hospitalizations in the cardio-renal phenotype.
Current guidelines do not recommend BBs for HFpEF unless required for comorbid conditions, such as AF. In HFpEF patients, BB use should be reviewed and alternatives, especially those with cardio and/or renal benefits, should be prioritized in the management of comorbidities, particularly hypertension. The widespread use of BBs in HFpEF despite lack of clear benefit or guideline endorsement underscores the need for prospective randomized trials to clarify their role in this population.
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