Angiotensin receptor neprilysin inhibitor in chronic heart failure and comorbidity management: Indian consensus statement

Abstract

Heart failure (HF) is a significant public health concern characterized by notable rates of morbidity and mortality. Multimorbidity, ranging from 43% to 98% among HF patients, significantly impacts prognosis and treatment response. HF management requires a holistic approach, including guideline-directed medical therapy. Sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) is a cornerstone of HF treatment, supported by robust evidence from large-scale clinical trials across different levels of left ventricular ejection fraction. The recommendations presented in this paper have been developed by a group of cardiologists in India who convened in expert opinion meetings to discuss the utilization of ARNI in chronic HF patients with five different comorbid conditions like type 2 diabetes mellitus (T2DM), chronic kidney disease, myocardial infarction (MI), obesity, and hypertension. Key focus areas include initiation, dose titration, and management across different HF phenotypes and comorbidities. Emphasis is placed on the efficacy of ARNI irrespective of glycemic status in the T2DM population, its role in HF patients with obesity, and addressing challenges related to renal function decline and hyperkalemia. Additionally, the document highlights ARNI’s potential benefits in hypertensive and post-MI HF patients, alongside observations on the obesity paradox in HF prognosis. Overall, these recommendations aim to optimize ARNI therapy in HF patient populations with different comorbidities, addressing specific challenges and considerations to improve outcomes and quality of life.

Plain language summary

Angiotensin receptor neprilysin inhibitor (ARNI) in chronic heart failure and comorbidity management: Indian consensus statement

Heart failure (HF) is a significant public health concern characterized by notable rates of morbidity and mortality. Multimorbidity, ranging from 43% to 98% among HF patients, significantly impacts prognosis and treatment response. HF management requires a holistic approach, including guideline-directed medical therapy (GDMT). Sacubitril/valsartan (ARNI) is a cornerstone of HF treatment, supported by robust evidence from large-scale clinical trials across different levels of left ventricular ejection fraction (LVEF). The recommendations presented in this paper have been developed by a group of cardiologists in India who convened in seven advisory board meetings to discuss the utilization of ARNI in chronic HF (CHF) patients with different comorbid conditions like Type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), myocardial infarction (MI), obesity, and hypertension. Key focus areas include initiation, dose titration, and management across different HF phenotypes and comorbidities. Emphasis is placed on the efficacy of ARNI irrespective of glycemic status in the T2DM population, its role in HF patients with obesity, and addressing challenges related to renal function decline and hyperkalemia. Additionally, the document highlights ARNI’s potential benefits in hypertensive and post-MI HF patients, alongside observations on the “obesity paradox” in HF prognosis. The paper underscores the importance of accurate biomarkers and imaging in HF diagnosis and monitoring. Overall, these recommendations aim to optimize ARNI therapy in HF patient populations with different comorbidities, addressing specific challenges and considerations to improve outcomes and quality of life.

Keywords

ARNI chronic heart failure chronic kidney disease sacubitril/valsartan type 2 diabetes mellitus

Introduction

Heart failure (HF), a major public health concern, leads to frequent hospitalizations and significant healthcare expenditures. In India, the HF burden differs from Western countries. As per Indian and global HF registries,^1,2 Indian HF patients are typically 10 years younger, with a male-female ratio of 70:30, contrasting with the more equal ratio in the United States and Africa. Rheumatic heart disease contributes 8%–10% to India’s HF burden but is less prevalent in the West. Type 2 diabetes is more prevalent among Indians, as shown by the Trivandrum Heart Failure Registry.¹ Additionally, HF prognosis is poorer in India, with an in-hospital mortality rate of 8.4%,¹ compared to 4% in the Acute Decompensated HEart Failure National REgistry (ADHERE) of the United States.³

HF often comes with cardiac/non-cardiac comorbidities, complicating diagnosis and management and leading to worse outcomes and higher hospitalization rates.⁴ The prevalence of multimorbidity in HF patients varies widely, ranging from 43%⁵ to 98%,⁶ and shows geographic variation. More than 85% of HF patients have ⩾2 additional comorbidities.⁷ Incidence and prevalence of multimorbidity in Asia have shown increasing trends with young HF patients having a greater number of comorbid conditions compared to their counterparts in Western countries.⁸ Data from the Indian registry reveals a growing burden of HF attributed to population aging and comorbidities.⁹ In a prospective observational study at a north Indian community hospital, major comorbidities comprised type 2 diabetes mellitus (T2DM; 60.7%), arterial hypertension (51%), anemia (54%), chronic kidney disease (CKD; 29%), atrial fibrillation (16%), and hypothyroidism (9%).¹⁰

Left ventricular ejection fraction (LVEF) is crucial in HF for diagnosis, prognosis, treatment, and trial inclusion. Comorbidity distributions vary among LVEF subtypes, affecting prognosis across the LVEF spectrum. Data from an HF registry in South India revealed that T2DM was predominant in heart failure with reduced ejection fraction (HFrEF) and heart failure with mildly reduced ejection fraction (HFmrEF), while systemic hypertension was prevalent in heart failure with preserved ejection fraction (HFpEF), alongside other significant comorbidities such as coronary artery disease (CAD), chronic obstructive pulmonary disease, and CKD.¹¹

Presence of comorbid conditions may impact the response to therapy and risk-benefit balance. Guidelines highlight the gap in optimizing pharmacological treatment for HFrEF patients with comorbidities.^12,13 While guideline-directed medical therapy (GDMT) is advantageous for comorbidities, up-titration may be an issue hence reducing the effectiveness, safety, and complications.¹⁴ In the EPIC-HF trial, T2DM (p = 0.02), hypertension (p = 0.003), and CKD (p = 0.047) were each associated with a lower probability of intensifying GDMT.¹⁵

A persistent high burden of comorbidity in HF patients, increasing with age, correlates with higher rates of HF hospitalization (HFH) and all-cause mortality.^5,16 In the international REgistry to assess medical Practice and lOngitudinal obseRvation for Treatment of Heart Failure (REPORT-HF) study involving 18,528 patients, 1-year mortality rose from 13% for patients without comorbidities to 26% for those with five or more comorbidities.⁷ The comorbidity prevalence in selected HF trials and registries has been listed in Tables 1 and 2. Screever et al. investigated comorbidity associations with composite clinical outcomes of HFH and cardiovascular death in HF patients over a 15-year period, from 2002 to 2017. They found that obesity had a high prognostic impact while comorbidities like CAD, CKD, and hypertension showed moderate impact, and the comorbidity of T2DM showed a low impact, on the clinical outcomes in the 2017 population compared to 2002. Additionally, higher comorbidity burden was significantly linked to increased risk for HFH and all-cause mortality in both the 2002 and 2017 cohorts.¹⁶ The prognostic impact of the comorbidities with the composite outcomes has been illustrated in Figure 1.

Table 1.

The prevalence of comorbidities in selected trials of HF.

Clinical trials	T2DM (%)	Hypertension (%)	ACS/myocardial infarction (MI)
HFrEF trials
PARADIGM-HF¹⁷	35	71
SHIFT¹⁸	30	67	56% (MI)
HF-ACTION¹⁹	32	75.9	—
SENIORS²⁰	26	67	49% (MI)
SOLVD²¹	15	42.8	66.3% (MI)
MERIT-HF²²	25	56	53%
CHARM-Alternative²³	27.4	5.7	62.1%
HFpEF trials
I-Preserve²⁴	27	88	23%
PEP-CHF²⁵	21	79	27%
DIG-PEF²⁶	27.4	62	49.6%
CHARM-PRESERVED²⁷	28.3	55.1	52.2%

ARNI, angiotensin receptor neprilysin inhibitor; CHARM-Alternative, Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity–Alternative Trial; CHARM-PRESERVED, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity–Preserved; DIG-PEF, Digitalis Investigation Group–Preserved Ejection Fraction; DIG-REF, Digitalis Investigation Group–Reduced Ejection Fraction Trial; HF-ACTON, Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; I-preserve, Irbesartan in Heart Failure with Preserved Ejection Fraction Trial; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; MI, myocardial infarction; PARADIGM-HF, Prospective Comparison of ARNI with Angiotensin Converting enzyme inhibitor (ACEi) to Determine Impact on Global Mortality and Morbidity in Heart Failure; PEP-CHF, Perindopril in Elderly People with Chronic Heart Failure; SENIORS, Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure; SHIFT, Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial; SOLVD, Studies of Left Ventricular Dysfunction; T2DM, type 2 diabetes mellitus.

Table 2.

Registry data on the prevalence of comorbidities in HF.

HF registry	T2DM	Hypertension	CKD	ACS/CAD/MI
Global registry
GWTG-HF²⁸	44.0%	78.45%	3.9% (dialysis)	49.37% (CAD)
GWTG-HF²⁸	44.0%	78.45%	21% (non-dialysis)	19.5% (prior MI)
Swedish Heart Failure Registry²⁹	23.9%	51.5%	43.9%	—
Spanish HF registry data (RICA)³⁰	45.3%	86%	61%	23% (prior MI)
Indian registry
National Heart Failure Registry³¹	42.3%	48.9%	8.5%	71.79%
Trivandrum Heart Failure Registry³²	55.2% (HFrEF)	58.8% (HFrEF)	17.3% (HFrEF)	74.6% (HFrEF)
	59.3 (HFmrEF)	57% (HFmrEF)	20.5% (HFmrEF)	79.3% (HFmrEF)
	48% (HFpEF)	54.8% (HFpEF)	16.8% ( HFpEF)	56.3% (HFpEF)
ICC National Heart Failure Registry³³	51.53%	52.27%	14.81%	75.44% (CAD)
Medanta Registry³⁴	59.1% (HFrEF)	48.9%	—	77.8% (CAD)32% (MI)

CAD, coronary artery disease; CKD, chronic kidney disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; MI, myocardial infarction; GWTG-HF, Get With the Guidelines–Heart Failure; ESC-HFA, European Society of Cardiology Heart Failure Association; T2DM, type 2 diabetes mellitus.

Figure 1.

Trend in the prognostic importance of comorbidities in HF patients from 2002 to 2017.

Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is a well-established and well-accepted pillar drug in HFrEF GDMT. Large randomized clinical trials have proven the benefits of ARNI in HF across LVEF spectrum.³⁵ However, large registries show a sluggish adoption of ARNI in clinical practice, with only 2.3% of patients utilizing it 1 year following Food and Drug Administration approval.²⁸ The National Heart Failure Registry showed that merely 47.5% of HFrEF patients received GDMT, with very minimal ARNI utilization observed in both HFrEF (4.8%) and HFmrEF (4.7%) patients.³¹ These studies indicate that there is an underutilization of ARNIs among HF patients in India, especially when considering various comorbidities that warrant attention.

Methodology

The scope of the current expert consensus is to provide an overview of the evidence and the expert opinion on role of ARNI in management of HF in patients with five comorbidities of T2DM, CKD, obesity, hypertension, and ACS. The expert opinion meeting was conducted in December 2023 with a group of cardiologists from across India. During the meeting, the experts reviewed available literature evidence and provided individual insights based on their experience in managing HF in patients with different comorbidities, with a primary focus on the role of ARNI in these patients. The structured discussions during the meetings addressed aspects including role of ARNI in HF patients with five comorbidities of T2DM, CKD, obesity, hypertension, and ACS, dosing of ARNI, and challenges with ARNI therapy. After thorough discussion and deliberation, the expert recommendations were developed, basis the insights from the meeting.

Diagnostic approaches in HF

According to 2022 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, diagnosing HF involves elevated levels of natriuretic peptides (NP), echocardiographic diastolic parameters like E/e′ ratio ⩾15, or other indications of increased filling pressures, or invasive hemodynamic measurement at rest or during exercise.^13,36,37 The diagnostic approaches that provide essential information for evaluating chronic HF, with considerations for specific comorbidities such as obesity, T2DM, and CKD have been enlisted in Tables 3 and 4. The diagnostic algorithm for suspected HF has been illustrated in Figure 2 and the guideline recommendation for the use of biomarkers for prevention diagnosis and risk stratification has been illustrated in Figure 3.

Table 3.

Diagnostic measures for HF.

Diagnostic measure	Threshold	Comments
Natriuretic peptides	BNP and NT-proBNP cut-offs: 35 and 125 pg/mL for ambulatory HF, and 100 and 300 pg/mL for hospitalized HF, respectively^38,39	• BNP or NT-proBNP levels are crucial in evaluating suspected HF cases• Elevated NP levels indicate HF, but factors like age, atrial fibrillation, diabetes, and CKD can affect results^39,40 • In obese patients, NP levels may not accurately reflect HF due to an inverse relationship with obesity.⁴¹ • Lower BNP cut-offs (e.g., 54 pg/mL for body mass index (BMI) >35 kg/m²) may be needed to maintain 90% sensitivity for HF diagnosis in obese individuals⁴²
Cardiac TroponinHigh-sensitivity (hs) cardiac troponin (cTn) hscTnT	Normal (hs Troponin T < 14 ng/L)Possible MI (hs Troponin T 14–30 ng/L)Probable MI (hs Troponin T > 30 ng/L)	• Serum troponin measurement at admission helps assess myocardial injury⁴³ • Significant elevation (>50% of upper limit of normal) or rapid increases >20% of initial value in 1–3 h) may suggest concurrent myocardial ischemia
Relative wall thickness	>0.42	• While the presence of concentric LVH supports HFpEF diagnosis, its absence does not rule out HFpEF⁴⁴
LA volume index	>34 mL/m² (SR)>40 mL/m² (AF)	• Left atrial enlargement indicates chronically elevated left ventricular filling pressure in the absence of atrial fibrillation or valvular disease⁴⁴
E:e′ ratio at rest	>9	• Invasive exercise testing for HFpEF demonstrates a sensitivity of 78% and a specificity of 59%• Using a cut-off of 13 yields lower sensitivity (46%) but higher specificity (86%)⁴⁴
Echocardiography	• Key for assessing cardiac function and crucial in HFpEF evaluation• In acute HF, echocardiographic measurement is recommended at the time of hospital admission, during hospitalization, and pre-discharge to assess the possibility of congestion, cardiac dysfunction, and mechanical causes of cardiac dysfunction⁴³ • Helps estimate elevated LV filling pressure and detect structural defects like LVH⁴⁴ • Useful in identifying abnormalities in T2DM like increased LV mass and diastolic dysfunction, even in asymptomatic cases⁴⁴ • LV mass increases with age, obesity, and dyslipidemia, easily identifiable through echocardiographic examination⁴⁴ • LVH is often detectable via echocardiography in CKD patients undergoing hemodialysis⁴⁵
Heart failure basis LVEF
Diagnosis of HFrEF and HFmrEF	• Elevated NP levels alongside structural heart issues like LVH aid in diagnosis.• EF measurement is conclusive in some cases
Diagnosis of HFpEF	• Challenging diagnosis, often involving multiple criteria.• E/e′ ratio exceeding 13.80 indicates heightened heart failure rehospitalization risk⁴⁶ • ESC recommends HFA-PEFF and H2FPEF scores for diagnosis.• H2FPEF score helps distinguish HFpEF from non-cardiac causes of dyspnea (Table 4)⁴⁷

AF, atrial fibrillation; BMI, body mass index; CKD, chronic kidney disease; E:e′, early diastolic transmitral flow velocity: early diastolic mitral annular tissue velocity; EF, Ejection fraction; ESC, European Society of Cardiology; HF, heart failure; HFpEF, heart failure preserved ejection fraction; LA, left atrial; LV, left ventricular; LVH, left ventricular hypertrophy; MI, myocardial infarction; NP, natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PA, pulmonary artery; SR, sinus rhythm; T2DM, type 2 diabetes mellitus; TR, tricuspid regurgitation.

Table 4.

H2FPEF scoring algorithms for HFpEF diagnosis.

	Clinical variable	Value	Points
H₂	Heavy	Body mass index >30 kg/m²	2
H₂	Hypertensive	2 or more hypertensive medicines	1
F	Atrial fibrillation	Paroxysmal or persistent	3
P	Pulmonary hypertension	Doppler echocardiographic estimated right ventricular systolic pressure >35mmHg	1
E	Elder	Age > 60 years	1
F	Filling pressure	Doppler echocardiographic E/e′ > 9	1
		H2FEPF score	Sum (0–9)

Source: Adapted from Abramov and Parwani.⁴⁷

Patients are categorized into low (0–1 points), intermediate (2–5 points), or high (6–9 points) probability of HFpEF based on the presence of comorbidities/variables, with points assigned accordingly.

HFpEF, heart failure preserved ejection fraction.

Figure 2.

Diagnostic algorithm for chronic HF patient.

Figure 3.

Guideline recommendations for the use of BNP or NT-proBNP for prevention, diagnosis, and risk stratification.

ARNI in HF patients with T2DM

ARNI is cornerstone of GDMT in patients diagnosed with HF, facilitating reverse cardiac remodeling and enhancing outcomes in HFrEF patients with T2DM. In a post hoc analysis of the PROVE-HF trial, focusing on a T2DM population (45.5%) with elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, ARNI initiation led to decreased NT-proBNP levels and enhanced LVEF over a 12-month period.⁴⁸

In the PARADIGM-HF study, patients with a history of diabetes mellitus had a higher risk of HFH and cardiovascular mortality compared to those with normal HbA1c levels (hazard ratio (HR): 1.64; 95% CI: 1.44–1.88; p < 0.001). However, the benefit of ARNI, compared with enalapril, in reducing the risk of primary composite was consistent across the range of HbA1c (HR: 0.68 (95% CI: 0.56–0.83), for normoglycemia; HR: 0.76 (95% CI: 0.63–0.91) for prediabetes; HR: 0.87 (95% CI: 0.77–0.98) for diabetes).⁴⁹

A post hoc analysis of the PARADIGM-HF trial demonstrated that HFrEF patients with T2DM treated with ARNI showed better glycemic control and insulin treatment use than those treated with enalapril during the 12-month follow-up period. HbA1c concentrations decreased by 0.16% in the enalapril group and 0.26% in the ARNI group (between-group reduction 0.13%, 95% CI: 0.05–0.22, p = 0.0023), while new use insulin and oral antihyperglycemic drugs reduced 29% (HR: 0.71, 95% CI: 0.56–0.90, p = 0.0052) and 23% (HR: 0.77, 95% CI: 0.58–1.02, p = 0.073) respectively, in the ARNI group.⁵⁰ Similarly, among patients with HFpEF and diabetes in PARAGON-HF trials, ARNI lowered HbA1c compared with valsartan (reduced by 0.24%, p < 0.001), and initiation of insulin therapy.⁵¹

In a combined analysis of PARAGON-HF and PARADIGM-HF, ARNI treatment noted a consistent effect on glycemia across the spectrum of LVEF with a 25% greater reduction in the initiation of new insulin therapy (HR: 0.75, 95% CI: 0.63–0.89, p = 0.001) compared to valsartan or enalapril.⁵¹

ARNI in HF patients with CKD

Implementing ARNI in patients with HF and CKD remains an important research focus owing to the warranted advantages and risks. Evidence indicates that the use of ARNI might provide significant benefits to this population. ARNI treatment not only provides cardioprotection but also exerts renoprotective effects in HF patients. Enhanced NP level, facilitated by ARNI, promotes natriuresis and increases intraglomerular pressure and glomerular filtration rate (GFR) by boosting kidney perfusion and predominantly dilating afferent arteries. These effects likely shield the kidneys during reduced perfusion caused by an acute decrease in cardiac output.

ARNI in HF patients with non-dialysis CKD

ARNI provides cardiovascular benefits in patients with CKD and HF. In the CKD subgroup of the PARADIGM-HF study, (estimated glomerular filtration rate (eGFR): 30–60 mL/min/1.73 m²). ARNI reduced cardiovascular death risk by 24% and HFH risk by 21% compared to ACEi treatment.⁵² In a combined analysis of HFrEF and HFpEF patients from the PARADIGM-HF and PARAGON-HF trials, ARNI demonstrated reduced composite renal outcomes (HR: 0.56, 95% CI: 0.42–0.75, p < 0.00) and slowed eGFR decline compared to renin angiotensin aldosterone system inhibitor (RAASi).⁵³

Studies demonstrating renoprotection effect of ARNI in non-dialysis patients with CKD and HF have been listed in Table 5.

Table 5.

Summary of trial with renoprotection with ARNI.

Study trial	Patients	Subgroups	Treatment	Summary for renoprotection
PARADIGM-HF⁵²	HFrEF (EF ⩽ 35%)		ARNI vs enalapril	Post hoc composite outcome (end-stage renal disease or a ⩾50% decrease in the eGFR from baseline): ARNI betterUACR reduction: enalapril better
		+eGFR < 60		Post hoc renal composite outcome: comparable
		+eGFR ⩾ 60		Post hoc renal composite outcome: comparable
		+UACR ⩾ 3.5		Post hoc renal composite outcome: comparable
		+UACR < 3.5		Post hoc renal composite outcome: comparable
PARAGON-HF⁵³	HFpEF (EF ⩾ 45%)		ARNI vs valsartan	Composite outcome: ARNI bettereGFR preservation: ARNI better
		+eGFR < 60		Composite outcome: ARNI better
		+eGFR ⩾ 60		Composite outcome: ARNI better
PARAMOUNT⁵⁴	HFpEF (EF ⩾ 45%)		ARNI vs valsartan	eGFR preservation: ARNI betterUACR reduction: valsartan better

ARNI, angiotensin receptor neprilysin inhibitor; eGFR, Estimated glomerular filtration rate; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; UACR, urine albumin-creatinine ratio.

Renal dysfunction can impact the drug exposure for LBQ657 which is the active metabolite of the prodrug sacubitril but has no effect on the exposure of sacubitril and valsartan. There was no significant difference in LBQ657 exposure among patients with mild renal dysfunction (eGFR 60–90 mL/min/1.73 m²) compared to patients with normal renal function. But, exposure increased by 2.29 times in moderate renal dysfunction (eGFR 30–60 mL/min/1.73 m²), by 2.90 times in patients with severe renal dysfunction (eGFR < 30 mL/min/1.73 m²), and by 3.27 times in non-dialysis end-stage renal disease (ESRD) patients. Moreover, LBQ657 half-life increased from 12 h to 21.1, 23.7, and 38.5 h in mild, moderate, and severe renal dysfunction, respectively.^55,56 Dose recommendation for ARNI in CKD patients is mentioned in Table 6.

Table 6.

Dosing guidance for ARNI in CKD.

CKD patients	Cardio condition	eGFR	Initial dose	Target doses
Non-dialysis CKD	HF	eGFR ⩾ 60 mL/min/1.73 m²	50 mg BID	200 mg BID
Non-dialysis CKD	HF	eGFR < 60 mL/min/1.73 m²	25–50 mg BID	200 mg BID
Maintenance dialysis	HF	—	25–50 mg QD	100–150 mg QD to BID

Source: Adapted from Gan et al.⁵⁶

ARNI, angiotensin receptor neprilysin inhibitor; BID, twice daily; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure; QD, once daily.

Managing HF in CKD patients is challenging as treatment of HF leads to worsening kidney parameters. The use of ARNI may lead to increased serum potassium and creatinine levels because of its effect on the RAAS. Clinical data on ARNI in patients with rapidly declining renal function is lacking. Hyperkalemia was reported in 12.3% of the PARADIGM-HF patients. In the PARADIGM-HF study (excluding patients with eGFR < 30 mL/min/1.73 m²), the ARNI treatment group demonstrated lower serum potassium levels compared to the enalapril group,¹⁷ and hyperkalemia incidence was significantly lower in the ARNI group compared to the valsartan group in PARAGOAN-HF study (13.2% vs 15.3%, p = 0.048).⁵⁷

In the PARADIGM-HF study, the ARNI group had a significantly lower risk of increased serum creatinine compared to the enalapril group.¹⁷ A 2020 meta-analysis presented in the American Society of Nephrology also showed a 14% reduction in the risk of elevated serum creatinine with ARNI versus RAASi (odds ratio: 0.86; 95% CI: 0.78–0.95, p = 0.002).⁵⁸

ARNI in HF patients with CKD undergoing dialysis

ARNI is not recommended in patients with severe renal dysfunction, but it may have a cardioprotective role in ESRD patients undergoing dialysis. A systematic meta-analysis aimed at investigating the treatment effects of ARNI in patients with HF and ESRD on maintenance dialysis demonstrated significant clinical benefits with 36% risk reduction for all-cause mortality, 29% risk reduction of HFH, and an increase in LVEF by 8% without increasing the risk of adverse events of severe hyperkalemia, and symptomatic hypotension.⁵⁹ It significantly improved and stabilized the cardiac function of ESRD patients with HFpEF undergoing dialysis.⁶⁰ A retrospective analysis of 23 HFrEF patients with ESRD on dialysis showed that ARNI (mean dose 90 ± 43 mg/day at baseline) significantly enhanced LVEF.⁶¹ ARNI group had a more pronounced decrease in cardio-markers compared to the no ARNI group among patients undergoing dialysis.⁶²

In a study from South India involving HFrEF patients with advanced CKD treated with ARNI, there was a significant reduction in hospitalizations for breathlessness, improvement in NYHA and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and decreased NT-proBNP levels after 6 months, with no significant change in eGFR.⁶³ ARNI at a dose of 100–150 mg BID was safe and tolerable for hemodialysis patients.^61
–63

Despite their high-risk status, patients with ESRD are often excluded from crucial HF clinical trials, leading to a scarcity of data on HF management in dialysis patients. Caution is advised when using ARNI in this group of patients, and its efficacy requires further validation through extensive studies.

ARNI in HF patients with obesity

Obesity initiates cardiomyopathy, marked by left ventricular hypertrophy and primarily diastolic dysfunction, resulting in HFpEF. With prolonged obesity, left ventricular systolic function declines, leading to HFrEF.⁶⁴ The risk of developing HF is two times greater in patients with a BMI > 30 kg/m² in comparison with healthy, non-obese individuals.⁶⁵ In the analysis presented by Kristensen et al.⁶⁶ Asian populations from the PARADIGM HF had the lowest BMI (24 ± 4 kg/m²) and had the highest risk of primary composite of cardiovascular death and HFH compared to the Western counterparts. Despite the elevated risk of cardiovascular disease (CVD) associated with increased BMI and obesity, recent studies propose an inverse correlation between obesity and the prognosis of established CVD, termed “the obesity paradox.” Multiple authors have validated the presence of the obesity paradox in large-scale HF clinical trials, indicating that patients with higher BMI tend to have better prognoses compared to those with lower BMI values. A registry study involving 108,927 patients with acute HF showed a 10% reduction in mortality for every 5-unit increase in BMI.⁶⁷ Obesity paradox exists in HFrEF⁶⁸ and HFpEF patients. In HFpEF patients, adverse outcomes were highest in both the lowest and highest BMI categories, showing a U-shaped relationship with BMI.⁶⁹ However, obesity paradox was not observed in T2DM patients.⁷⁰

BMI doesn’t fully capture body composition or fat distribution. While central obesity, measured by waist circumference, is a major CVD risk factor, its higher value is linked to a better prognosis in HFrEF patients. Streng et al. found that increased BMI correlates with better outcomes across HF ejection fractions, supporting the obesity paradox. Conversely, a higher waist-to-hip ratio doubles the risk of all-cause mortality, especially in women, independent of BMI and other factors.⁷¹

In the Swedish HF Registry, where 24% of patients were obese, ARNI use was linked to lower mortality, irrespective of obesity status. Notably, obese patients exhibited a stronger association with reduced cardiovascular death and achieved ⩾100% of the target dose of 200 mg BD (46%) compared to non-obese individuals.⁷² In a multicenter retrospective study involving 721 ARNI HFrEF patients, no significant differences in HF-related hospitalizations or all-cause mortality were observed among individuals across the three standard BMI groups.⁷³ In another clinical study of HFrEF obese patients, having a BMI of 30 kg/m² or higher was not identified as a predictor of elevated mortality risk.⁷⁴

In a retrospective Indian study of HFrEF patients with a BMI of 31 kg/m², ARNI was deemed safe in outpatient settings and associated with significant clinical improvement. This was evidenced by enhancements in the New York Heart Association (NYHA) class and KCCQ score and a notable reduction in NT-proBNP levels.⁷⁵ The sub-analysis of the PARADIGM-HF trial among the Asians with mean BMI (24 ± 4 kg/m²) showed similar treatment effects as the overall study population with mean BMI (28.1 ± 5.5 kg/m²).⁷⁶

ARNI for HF patients with hypertension

ARNI in HF patients with hypertension

Clinical evidence strongly supports the superiority of ARNI over ACEi and its favorable tolerance in patients with hypertension and HFrEF. In the PARADIGM-HF trial, the benefit of ARNI over enalapril remained consistent across all baseline systolic blood pressure (SBP) categories for all outcomes.⁷⁷ In post hoc analysis of the PARAGON-HF trial, ARNI effectively lowers BP in HFpEF patients with apparent resistance, including those with elevated SBP despite treatment with at least four antihypertensive drug classes, including an Mineralocorticoid receptor antagonist (MRA).⁷⁸

Addressing the challenge of hypotension in HF patients

Despite studies indicating poorer prognosis in patients with low SBP, the PARADIGM-HF study revealed that ARNI was superior to enalapril in reducing mortality and morbidity in patients with persistently low SBP after treatment. Additionally, patients in the lowest SBP category experienced a similar degree of benefit from ARNI as the overall trial population.⁷⁷ In PARADIGM-HF, patients with low baseline SBP experienced more hypotension-related adverse effects, although the proportion of those assigned to ARNI and discontinuing due to hypotension was not substantial.⁷⁷ In the TITRATION trial, patients with lower SBP (100–110 mmHg) achieved higher treatment success rates with gradual up-titration (6 weeks; ~80%) compared to rapid up-titration (~69%). Similar trends were noted for “tolerability success” in maintaining the target dose.⁷⁹ These findings imply that clinicians should not overlook initiating ARNI due to low SBP, as it significantly reduces morbidity and mortality in HFrEF patients.

ARNI as antihypertensive in pre-HF stage

Hypertension contributes to the onset of HF characterized by both reduced and preserved ejection fraction. The ACC/AHA HF guidelines define stages of HF, emphasizing the development and progression of the disease. Stage A refers to the patients at risk for HF but without symptoms, structural heart disease, or cardiac biomarkers of stretch or injury (e.g., patients with hypertension) while stage B refers to pre-HF stage with no symptoms or signs of HF but objective evidence of structural heart disease.¹³ Sacubitril/valsartan is not approved for the treatment of hypertension in Europe or in the United States, while it was approved as an antihypertensive agent in China and Japan.⁷⁹ 2020 International Society of Hypertension global practice guidelines on hypertension mentioned that ARNI is indicated for HFrEF as an alternative to RAASi and is suitable for hypertensive patients.^80,81 This approach may also be applicable to HFpEF patients, although the optimal treatment strategy is uncertain.

Few studies have been published that demonstrate the blood pressure-lowering effectiveness of ARNI in patients with essential hypertension. ARNI effectively lowers both SBP and DBP in grade I to III hypertension (office BP ⩾180/110 mmHg), with or without CKD, without notable adverse effects like angioedema. Its effects persist for 24 h, including during nocturnal and morning periods.⁸² In a placebo-controlled, dose-ranging study of ARNI involving 389 hypertensive subjects from Asian countries, including Japan and China, ARNI demonstrated a dose-dependent reduction in BP. Notably, Asian patients experienced a significantly greater reduction in BP, particularly at lower doses, compared to the European population. The mean differences in clinic DBP change from baseline were −7.84, −7.29, and −8.76 mmHg for ARNI doses of 100, 200, and 400 mg, respectively, compared to placebo (all p < 0.0001). This study marks the first time that all three doses of ARNI significantly reduced both clinic and 24-h ambulatory BP in Asian patients with hypertension.⁸³

ARNI in HF patients with patients with acute coronary syndrome

Acute myocardial infarction (MI) triggers pathophysiological changes, including myocardial necrosis, edema, and microvascular damage, leading to adverse events like ventricular remodeling and HF. Destructive ventricular remodeling after ischemic injury significantly contributes to the progression of HFrEF.⁸⁴ Given the substantial advantages of ARNI in treating HFrEF, including cases with an ischemic origin, numerous trials have explored the possible application of ARNI in acute MI.

In the SAVE-STEMI trial, ARNI therapy for 6 months led to significantly greater improvement in LVEF, LV end-diastolic diameter, and LV end-systolic diameter.⁸⁵ The PARADISE-MI (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI) trial comparing ARNI with ramipril in AMI patients, reported no significant reduction in CV death or HFH with ARNI.⁸⁶ However, patients on ARNI exhibited improvements in LV mass index, lateral tissue Doppler velocity, and tricuspid regurgitation peak velocity compared to those on ramipril, suggesting potential benefits in limiting LV enlargement and enhancing diastolic function post-AMI.⁸⁷

Nevertheless, in PARADIGM-HF, where 43.3% had a history of MI, and 57.1% had CAD, ARNI outperformed enalapril in reducing CV death or HFH and the composite of CV death, non-fatal MI, angina hospitalization, or coronary revascularization. Additionally, ARNI treatment reduced mortality in CAD patients compared to enalapril (20.3% vs 17.1%).⁸⁸ In the PARADISE-MI trial subset, ARNI showed a decreased risk of coronary outcomes compared to ramipril in patients with acute myocardial infarction (AMI) with LV systolic dysfunction or pulmonary congestion (HR: 0.86, 95% CI: 0.74–0.99, p = 0.04), over a median follow-up of 22 months.⁸⁹ A meta-analysis assessing the effectiveness of ARNI in reducing major adverse cardiac events and improving LV remodeling in acute MI patients with HF demonstrated that ARNI treatment enhanced LVEF and reduced LV remodeling parameters more significantly than controls. Additionally, ARNI led to lower NT-proBNP levels and greater improvements in exercise capacity.^90,91

Expert recommendations for the use of ARNI in HF

The structured discussions and the expert opinions based on the clinical experience of the cardiologists during the meeting were collated and the insights were used to develop expert recommendations for the use of ARNI in HF patients with comorbidities. These recommendations have been summarized in Table 7.

Table 7.

Summary of expert recommendations.

Comorbidity	Key points	Recommendation for ARNI
—	Diagnosis of HF	• The determination of LVEF is an essential step, especially in diagnosis of HFrEF• It is recommended that BNP or NT-proBNP be utilized for evaluating suspected HF, adhering to specific cut-off values as outlined in the guidelines• Elevated NP and structural heart signs should be used to diagnose HFrEF and HFmrEF• Echocardiography should be prioritized for assessing cardiac function in chronic HF and HFpEF evaluation• Employ H2FPEF scores for diagnosing HFpEF, aiding in distinguishing it from non-cardiac causes of dyspnea• NPs alone cannot establish risk stratification in obese population due to the lack of BMI-based cut-offs for HF diagnosis• Evaluate additional biomarkers alongside BNP and NT-proBNP for diagnostic or prognostic utility in obese HF patients
HF patients With T2DM	ARNI initiation across HF phenotype	• ARNI is recommended as a first-line treatment over RAASi, particularly following hospitalization for exacerbated HFrEF, with a preference for initiation during the pre-discharge period• Consider ARNI along with other GDMT pillars, across various LVEF in T2DM patients• ARNI provides benefits irrespective of glycemic status• ARNI aids in enhancing glycemic control in diabetic HFrEF patients
	Dosing	• Dose adjustment consideration is not necessary for ARNI initiation in patients with T2DM• The initiation and titration dose is determined by the patient’s hemodynamic stability and renal function indicators, such as BP, eGFR, serum creatinine, and serum potassium levels• Clinicians should consider the potential benefits of ARNI therapy, including improved glycemic control and reduced reliance on insulin or other hypoglycemic drugs in T2DM patients• Initiate ARNI at 50 or 100 mg twice daily, increasing to 200 mg twice daily over 6 weeks if SBP is ⩾100 mmHg for the 50 mg starting dose and over 3 weeks for the 100 mg starting dose
HF patients with CKD (non-dialysis)	Renoprotective and cardioprotective effect	• ARNI should be recommended for non-dialysis CKD patients with heart failure• Use of ARNI in CKD patients reduces cardiovascular risk and mortality compared to RAASi• ARNI can provide renoprotection with reduced risk of serious adverse renal outcomes and slowed decline in eGFR, compared with RAASi
	Dosing	• Dose adjustment may not be required in HF patients with mild to moderate renal impairment• For moderate to severe renal dysfunction, start with 25–50 mg BID, adjusting based on BP, and titrate gradually over 2 weeks
	Addressing challenges of declining renal function	• Regularly monitor renal function.• Follow RAASi protocols for declining eGFR with ARNI initiation• Maintain ARNI if creatinine increases by ⩽30% from baseline. Adjust dosage of ARNI if creatinine exceeds baseline by 30% and investigate underlying cause• Discontinue ARNI if creatinine increases by ⩾50% from baseline and investigate underlying cause
	Addressing challenges of hyperkalemia	• Switch to ARNI after potassium normalization for patients facing hyperkalemia with RAASi therapy• Consider stopping potassium supplementation and MRA if hyperkalemia (serum potassium ⩾5.5 mmol/L) occurs• Potassium binders may be considered to normalize potassium levels in case of severe hyperkalemia (serum potassium ⩾6 mmol/L)
HF patients with CKD undergoing dialysis	Use of ARNI	• ARNI should be used cautiously in patients with severe renal dysfunction• ARNI may be initiated at low dose of 50 mg twice daily and gradual titrate to 100–200 mg twice daily based on patient tolerance• Careful monitoring of BP and renal function is recommended
HF patients with obesity	Use of ARNI	• ARNI is equally effective in HFrEF patients with obesity among the Asian population (BMI ⩾ 25 kg/m²) comparable to the Western population (BMI ⩾ 30 kg/m²)
	Dosing	• In obese HFrEF patients, dose adjustment based on BMI is not necessary• Obese patients can tolerate 200 mg BD better than general population
HF patients with hypertension	Use of ARNI	• ARNI usage is associated with significant blood pressure reduction• The benefits of ARNI over enalapril are consistent across all baseline SBP (⩾100 mmHg) for the reduction in risk of cardiovascular mortality and hospitalization
	ARNI as hypertensive	• ARNI may be considered a hypertensive drug but is not approved in India
	Addressing challenge of low BP (SBP ⩽ 100)	• Low SBP should not be a reason for stoppage or not initiation of ARNI• For SBP < 100 mmHg or hypotension symptoms, identify and treat the underlying cause of hypotension like adjusting dose of diuretic and antihypertensive drugs• If hypotension persists, ARNI dose reduction or temporary stoppage may be considered
Post-MI HF patients	Use of ARNI	• ARNI may be used in post-MI patients with an LVEF ⩽40% with pulmonary congestion
	Dosing	• No dose adjustment needs to be considered for initiation of ARNI in these subsets of patients• For patients on prior RAASi, replacement with ARNI is recommended with a consideration for 36 h washout period before starting ARNI• Recommended initiation dose is 100 mg and titrate to 200 mg twice daily or maximum tolerated dose gradually

ARNI, angiotensin receptor neprilysin inhibitor; BMI, body mass index; BNP, B-type natriuretic peptide; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GDMT, guideline-directed medical therapy; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NP, natriuretic peptide; NT-proBNP, NT-pro-brain natriuretic peptide; RAASi, renin angiotensin aldosterone system inhibitor; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus.

Conclusion

In conclusion, the challenges of HF burden in India in relation to the Western countries are that Indian patients are younger, the prevalence of other comorbid diseases such as T2DM, hypertension, and ACS is higher and the survival rate is very low. Despite the proven benefits of ARNI therapy across the HF spectrum, its adoption remains low, especially in India. However, recommendations focus on the importance of ARNI initiation, dose titration, and management across different HF phenotypes and comorbid conditions like T2DM, CKD, ACS, obesity, and hypertension. Addressing challenges associated with ARNI therapy, such as hypotension, renal function decline, and hyperkalemia, is vital, especially among patients with non-dialysis CKD. Furthermore, it is essential to acknowledge and tackle the increasing prevalence of obesity. ARNI therapy may hold promise for managing HF in obese patients. The potential incorporation of ARNI into HF care and its ability to improve hometime emphasize its importance as the key pillar drug in HF management alongside enhancing both survival and quality of life in HF patients.

Footnotes

Acknowledgements

The authors express their gratitude to ARNI ACCORD Consensus Group who took part in the consensus meetings as their valuable contributions were instrumental in the development of the recommendations Dr Dilip MN, Dr Gopinath Parida, Dr Nirmal Jain, Dr Dheeraj Kumar, Dr Johan Christopher, Dr Somnath Mukjerjee, Dr Bappaditya Kumar, Dr Bhupen Desai, Dr Suman Bhandari, Dr Mohan Lal, Dr Vidhut Jain, Dr Akshay Bafna, Dr Bikramaditya Padhi, Dr Anil Sharma, Dr Pritam Kittey, Dr Chandrakanta Mishra, Dr Dipak Gaikwad, Dr Mahendra Prasad Samal, Dr Muhammed Mustafa, Dr Smit Shrivastava, Dr.Sebabrata Jana, Dr Arun Mohanty, Dr Bimit Kumar Jain, Dr Amit Chaturvedi, Dr Satish Suryavanshi, Dr Shravan Kumar, Dr Dilip Ratnani, Dr P. Krishnakumar, Dr Rana Rathore Roy, Dr Vikas Mishra, Dr Ramsagar Roy, Dr Abhilash T G, Dr Deepu Rajendran, Dr Sunil Lhila, Dr Rizwan Ul Haque, Dr Rohit mody, Dr Soumik Basu, Dr Soumik Ghosh, Dr Alok Singh, Dr Ajay Pandey, Dr Sunil Kumar Sharma, Dr Shilanjan Roy, Dr Shuvra Chakraborty, Dr Vineet Garg, Dr Vikas Kataria, Dr Kalpesh Hansora, Dr Mohit Mohan Singh, Dr Kaushik Manna, Dr C. B. Meena, Dr Aziz Khan, Dr Sameer Dani, Dr Arindam Pandey, Dr Nitin Gokhale, Dr Sachin Patil, Dr K Kannan. The authors thank Dr Preethi Naik, Dr Nitin Zalte, and Dr Amarnath Sugumaran from the Department of Medical Affairs, Cipla Ltd, Mumbai, for organizing and conducting the expert forum meetings. The authors also thank Dr Nidhi Gupta and Dr Punit Srivastava of Mediception Science Pvt. Ltd. for providing medical writing support and paid for by Cipla Ltd.

Declarations

ORCID iDs

Sanjay Mittal

Kamal Sharma

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