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Assessment of Prescription Pattern and Clinical Outcomes of Sacubitril/Valsartan in Heart Failure Patients with Reduced Ejection Fraction
*Corresponding author: Hemalatha Selvaraj, Professor and HOD, Department of Pharmacy Practice, Karpagam Academy of Higher Education, Coimbatore, Tamil Nadu, India. hemalatha.selvaraj@kahedu.edu.in
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Received: ,
Accepted: ,
How to cite this article: Selvaraj H, Purakkat A, Salih SR. Assessment of Prescription Pattern and Clinical Outcomes of Sacubitril/Valsartan in Heart Failure Patients with Reduced Ejection Fraction. J Card Crit Care TSS. doi: 10.25259/JCCC_1_2026
Abstract
Objectives:
The objective of the study is to examine the prescription patterns, efficacy, and tolerability of sacubitril/valsartan in patients with heart failure and reduced ejection fraction (HFrEF).
Material and Methods:
A 5-month prospective observational study took place at a hospital in Kerala, India, involving 50 HFrEF patients prescribed sacubitril/valsartan. Participants were aged >18 years and excluded if pregnant, diagnosed with cancer, or had stage 4/5 chronic kidney disease. Clinical parameters, including EF, blood pressure (BP), serum potassium, and creatinine, were evaluated at baseline and follow-up. Changes in left ventricular (LV) dysfunction and New York Heart Association (NYHA) functional class were additionally determined.
Results:
The cohort comprised 72% male and 28% female patients. Common comorbidities included diabetes (30%), hypertension (16%), and concurrent diabetes and hypertension (20%). Prescription patterns showed no sex-based variation, with doses of 50 mg and 100 mg used. From baseline to follow-up, a statistically significant enhancement was observed in EF (36.80 ± 5.993% to 38.12 ± 4.922%; P = 0.021), LV dysfunction (P = 0.002), and NYHA class (P = 0.005). Serum potassium, creatinine, and systolic/diastolic BP demonstrated no significant changes, though a slight, non-significant decrease in systolic BP was noted (131.57 ± 18.699 mmHg to 130.57 ± 11.554 mmHg). The treatment was well tolerated with no cases of significant symptomatic hypotension, hyperkalemia, or edema.
Conclusion:
In this short-term study, sacubitril/valsartan was effective in improving EF, LV function, and NYHA class in HFrEF patients, with good tolerability at the prescribed doses. Larger, long-term investigations are recommended for validating present results.
Keywords
Ejection fraction
Heart failure with reduced ejection fraction
Prescription pattern
Sacubitril/valsartan
Tolerability
INTRODUCTION
Heart failure (HF) occurs when the heart cannot pump enough blood to meet the metabolic needs. In India, there is an increased mortality rate due to HF. There is an increase in cardiovascular disease, particularly in urban areas of India. Increased blood pressure (BP) remains a major risk factor, followed by hyperlipidemia, diabetes, smoking, lack of exercise, and lack of healthy diets.[1]
Ejection fraction (EF) of a normal heart is about 55–65% per beat. In individuals with a lower EF, this could be as low as 40%. This may be due to the weakening of the heart muscle due to high BP, coronary artery disease (CAD), and other heart conditions. Breathing difficulty, edema in legs and ankles, and persistent cough are the major symptoms of HF.
HF impacts over 64 million individuals globally. Three groups of HF are distinguished by the left ventricular (LV) EF: HF patients with reduced EF (systolic HF), mildly reduced EF, and preserved EF (diastolic HF) fall into the following ranges: ≤40%, 41–49%, and ≥50%, respectively.[2]With a possible trend toward rising prevalence in the near future, HF remains a worldwide health threat. Globally, there were 56.19 million cases of HF, and several countries and territories showed an increase between 1990 and 2019, particularly in low-income countries.[3] Over-activation of neurohumoral processes is the basis for the pathophysiology of HF.[4]
Sacubitril/valsartan works by concurrently blocking the effects of angiotensin II and neprilysin. Inhibition of neprilysin improves the action of natriuretic peptides, and the suppression of the negative effects of angiotensin II improves the therapeutic effects in HF.[5] The PARADIGM-HF study has also proved that sacubitril/valsartan has lowered the mortality and morbidity rate in lower EF-patients. Overall, this drug was well tolerated, and the frequency of side effects was found to be lower.
A 20% reduction in death or hospitalizations due to heart-related problems was observed in population with sacubitril/valsartan treatment in the PARADIGM-HF study. A Class I recommendation in the European and United States HF guidelines and the approval from the “Food and Drug Administration” and “European Medicines Agency” were given to sacubitril/valsartan. Nevertheless, there are various studies demonstrating that the PARADIGM-HF study’s treatment patterns differed from those of real-world situations.[6-8]
Thus, the present observational clinical study was to evaluate the cardiovascular outcomes of the prescription pattern associated with sacubitril/valsartan treatment in HF patients with reduced EF.
MATERIAL AND METHODS
Study duration, period, and site
This was a prospective observational study performed at Daya General Hospital and Speciality Surgical Centre, a tertiary care facility in Thrissur, Kerala, between April 2025 and August 2025. The study included all HF patients of the cardiology department of the hospital. The Declaration of Helsinki’s principles (2013 revision) were followed in the current investigation. Institutional Ethics Committee at Daya General Hospital Limited provided the ethical approval under reference number: DH/ACADEMIC/DNB/07/25. Before enrollment, all participants were given written informed consent.
Study inclusion criteria
All the willing patients ≥18 years of age with low EF on sacubitril/valsartan therapy were included in the study.
Study exclusion criteria
All the patients ≤18 years of age, pregnant women, cancer patients, and patients with chronic kidney disease in the fourth or fifth stages were excluded from the study.
Data source and collection
The eligible patients were randomly selected, and the data were collected with the help of self-designed data collection forms. Serum sodium, serum potassium and level of LV dysfunction of patients with Sacubatril/Valsartan therapy were noted. This study assessed clinical outcomes of sacubitril/valsartan by collecting the EF of patients at baseline and at 5 months. The efficiency of the drug was analyzed by observing the LV dysfunction of the population at the baseline and after 5 months [Figure 1]. For evaluating the tolerability of sacubitril/valsartan combination therapy, patients’ symptoms of angioedema, hyperkalemia, and hypotension were examined. This study also examined the prescription pattern of sacubitril/valsartan in patients with HF who had a lower EF.
- Study plan.
Statistical analysis
Entering data in MS Excel and analyzing employing the Statistical Package for the Social Sciences v26 dependent sample t-test were used to compare the difference in mean score at baseline and follow-up.
RESULTS
This study was done in Daya General Hospital and Specialty Surgical Center, Thrissur, and studied for a period of 5 months. About 50 study participants satisfying the exclusion and inclusion criteria completed the study.
Demographic pattern of study population
Among the 50 study participants, male patients were 72% and female patients 28%.
In that, 40% belonged to the age group of 61–70 years old. However, 20% were in the 51–60 age range, and 24% were between the ages of 71 and 80 years. Only 8% of patients belong to 41–50 and 81–90 age groups.
About 30% of patients were non-smokers, and the rest were found to be smokers (70%). 82% and 18% found to be alcoholic and non-alcoholic in the study population, respectively. In this total study, participants 32% of patients were found to be aged with no occupation, 20% were housewives, 14% of them were doing business, 12% of them were teachers, and other 12% retired government employees; only 10% of them were working in the private sector.
Comorbidities pattern
In 50 patients, 30% were diabetes patients, 20% have both diabetes and hypertension. 16% of them had hypertension, 8% of them had asthma, and 6% were having both diabetes and asthma [Table 1].
| Characteristics of study participants | Number of participants (n=50) | Percentage |
|---|---|---|
| Age | ||
| 41–50 | 4 | 8 |
| 51–60 | 10 | 20 |
| 61–70 | 20 | 40 |
| 71–80 | 12 | 24 |
| 81–90 | 4 | 8 |
| Sex | ||
| Male | 36 | 72 |
| Female | 14 | 28 |
| Social habits | ||
| Smoking | 35 | 70 |
| Non-smoker | 15 | 30 |
| Alcoholic | 41 | 82 |
| Nonalcoholic | 9 | 18 |
| Occupational status | ||
| Working in private sector | 05 | 10 |
| Working as teacher | 06 | 12 |
| Doing business | 07 | 14 |
| Housewives | 10 | 20 |
| Retired government employees | 06 | 12 |
| Aged patients with no occupation | 16 | 32 |
| Comorbidities | ||
| Diabetes | 15 | 30 |
| Hypertension | 08 | 16 |
| Diabetes and hypertension | 10 | 20 |
| Asthma | 04 | 8 |
| Diabetes and Asthma | 03 | 6 |
In our present study, according to the clinical diagnosis, patients were prescribed at a dose of 50 mg and 100 mg. In 50 mg group of patients, 34% were males and 26% were females. In a 100 mg dose, prescribed 18% were males and 22% were females [Table 2].
| Characteristics of study participants (n=50) | 50 mg | Percentage | 100 mg | Percentage |
|---|---|---|---|---|
| Sex wise | ||||
| Male | 17 | 34 | 09 | 18 |
| Female | 13 | 26 | 11 | 22 |
| Age wise (years) | ||||
| 40–50 | 01 | 2 | 03 | 6 |
| 50–60 | 02 | 4 | 08 | 16 |
| 60–70 | 13 | 24 | 07 | 14 |
| 70–80 | 10 | 20 | 02 | 4 |
| 80–90 | 04 | 8 | - | - |
Prescription pattern of sacubitril/valsartan therapy
Our present study included 50 patients undergoing sacubitril/valsartan therapy; 60% of patients were taking 50 mg BD PO of the drug, while other 40% taking 100 mg BD PO of sacubitril/valsartan. There were 26 males and 24 females; in this, the dose distribution was found to be almost equal. 17 males received 50 mg, and only 9 males received 100 mg BD PO of the drug. While in the case of females, 50 mg BD PO was received by 13 females, and the remaining 11 of them received 100 mg BD PO of the drug.
Thirty of the fifty patients were on 50 mg BD PO, and the remaining 20 were on 100 mg BD PO. In these 30 patients undergoing 50 mg BD therapy, 13 of the patients were in the age group 60–70 years, 10 of them belonged to 70–80 age group, 4 of them from age group 80–90 years, while only 1 of them was of 40–50 years of age, and 2 remained in the age group 50–60 years.
In 20 patients treated with 100 mg BD PO, 8 were 50–60 years old, 7 were 60–70 years old, 3 were 40–50 years/old, and 2 were 70–80 years/old [Table 2].
Changes in biochemical and hemodynamic parameters
Table 3 presents the comparison of biochemical and hemodynamic parameters, serum creatinine, serum potassium, systolic BP, and diastolic BP between baseline and after 5 months of measurements among the study participants. No significant change in serum creatinine (P = 0.06) along with a strong positive correlation (r = 0.888) was observed. Serum potassium was found to be 3.6776 ± 0.86619 in the baseline and 4.200 ± 4.1754 at the 5th month. There was no statistically significant change (P = 0.380, r = 0.064) in the serum potassium. Systolic BP showed a slight decline from 131.57 ± 18.699 to 130.57 ± 11.554 (mean difference = 0.980, P = 0.601), with a moderate correlation (r = 0.708). Diastolic BP showed a minimal and statistically insignificant change from 80.59 ± 5.064 to 80.20 ± 2.441 (P = 0.598, r = 0.152). There was a statistically significant improvement in heart rate. It was found to be improved from 76.44 ± 11.19 to 74.20 ± 7.98 (P = 0.027, r = 0.788) with a positive correlation. These data were statistically analyzed using a paired t-test.
| Clinical parameters | Mean | P-value | Correlation |
|---|---|---|---|
| Serum creatinine (mg/dL) | |||
| Baseline | 1.016±0.24 | 0.060 | 0.888 |
| At 5th month | 1.0506±0.25 | ||
| Serum potassium (mEq/L) | |||
| Baseline | 3.6776±0.86 | 0.380 | 0.064 |
| At 5th month | 4.200±4.17 | ||
| Systolic BP (mmHg) | |||
| Baseline | 131.59±18.69 | 0.601 | 0.708 |
| At 5th month | 130.57±11.55 | ||
| Diastolic BP (mmHg) | |||
| Baseline | 80.59±5.06 | 0.598 | 0.152 |
| At 5th month | 80.20±2.44 | ||
| Heart rate (bpm) | |||
| Baseline | 76.44±11.19 | 0.027* | 0.788 |
| At 5th month | 74.20±7.98 | ||
Notable changes in LV dysfunction followed by the New York Heart Association (NYHA) class
In our study, the echocardiography was measured at the baseline and in the 5th month, and the LV dysfunction of patients was categorized into mild, moderate, and severe. At the baseline of the study, the patients were 18 in number in mild, 17 in moderate, and 15 in severe. At the 5th month of study, there were 23 patients in mild, 26 in moderate, and only 1 in severe. Using the McNemar test, p value was found to be 0.002, which is statistically significant [Table 4].
| Clinical characteristics of patients | Baseline No. of patients (n=50) | Percentage | At 5 months, number of patients (n=50) | Percentage | P-value |
|---|---|---|---|---|---|
| LV dysfunction | |||||
| Mild | 18 | 36.0 | 23 | 46.0 | 0.002* |
| Moderate | 17 | 36.0 | 26 | 52.0 | |
| Severe | 15 | 28.0 | 1 | 2.0 | |
| NYHA class | |||||
| I | 18 | 36.0 | 24 | 48.0 | 0.005* |
| II | 17 | 34.0 | 12 | 24.0 | |
| III | 14 | 28.0 | 14 | 28.0 | |
| IV | 1 | 2.0 | 0 | 0 | |
On considering the NYHA grade I-IV classification of patients it was found that eighteen patients were in class I at baseline, seventeen (class II), fourteen (class III), and one (class IV). By the first follow-up, redistribution occurred: there were still 24 patients in class I, 12 in class II, and 14 in class III. The McNemar test has been employed for statistical analysis, and statistically significant P-value was found to be 0.005 [Table 4].
Changes in EF
In our study, the mean EF was found to be elevated in patients taking sacubitril/valsartan from the baseline (36.80 ± 5.993) to the follow-up (38.12 ± 4.922) [Figure 2]. Paired t-test with Pearson correlation was used to analyze these data. The P-value was found to be 0.021, which is statistically significant.
- Ejection fraction.
Assessment of the tolerability of sacubitril/valsartan therapy
In our study population, it has been observed that there was no significant elevation in serum potassium, serum creatinine, and systolic and diastolic BP [Table 3]. This shows that the patients were well tolerated to the prescribed dose.
DISCUSSION
This prospective observational study estimated the cardiovascular effects of sacubitril/valsartan therapy in South Indian patients with low EF and high cardiovascular risk. The findings demonstrated clinically improvements in LV function, renal function, and hemodynamics, underscoring cardiovascular advantages of sacubitril/valsartan therapy in group of patients.
About 50 patients have been involved in this research. Among these, males made up most of the patients compared to females. Men develop CAD and experience acute myocardial infarctions (MIs) at a younger age and higher rate than premenopausal women. Remodeling and subsequent HF and reduced EF (HFrEF) are mostly caused by MI. Male sex is a risk factor for CAD on its own. Certain types of non-ischemic dilated cardiomyopathy, or associated with conditions like muscular dystrophy, show a male predisposition. Alcoholic cardiomyopathy is also significantly more prevalent in males, contributing directly to LV systolic dysfunction.[9,10] While testosterone can promote hypertrophy and may contribute to earlier development of hypertension and CAD, the cardioprotective effects of estrogen in pre-menopausal women are considered a more dominant differentiating factor. The protective effect of estrogen can be observed in the fact that its fall after female menopause is related to an increase in the risk of HF patients with reduced EF.[11-13]
A higher proportion of the age group in our study was in the 60–70-year age group, which shows that this age group is prone to developing complexity of the disease with comorbidities such as diabetes and hypertension and age-related physiological changes. Lesser proportion in the age group of 40–50 years indicates that disease patterns are typically associated with aging. Despite this, the early inception prevalence ratio paves the way for initiating preventive care and early diagnosis. While hypertension and diabetes are prevalent in both sexes, men often develop these conditions earlier in life. This leads to a longer duration of exposure to these damaging factors, contributing to end-organ heart damage. The combination of smoking and heavy alcohol use is also historically more common in males, both major risk factors for LV dysfunction.[14-15]
Societal norms and differences in symptom perception can lead to delayed diagnosis and treatment in men, allowing underlying conditions like CAD or cardiomyopathy to progress to a stage of significant systolic dysfunction before intervention.[16]
The pattern of prescription of sacubitril/valsartan was analyzed for about 5 months. Among 50 patients undergoing sacubitril/valsartan therapy, 60% of patients were taking 50 mg of the drug, while none of them received 200 mg dose of the drug. No dose up titration or down titration was found in these 50 patients within 5 months. If a patient is stable on a lower dose, further forced titration may not be mandatory if the higher dose is poorly tolerated. Decline in glomerular filtration rate (GFR), less compliant vasculature and attenuated baroreflex responses were seen in older aged patients. Polypharmacy in the aged population is frequently on diuretics, other antihypertensives, and higher prevalence of comorbidities also influences the dose titration. In this study, there was no evidence of hyperkalemia and hypotension states that patients were well tolerated to the prescribed doses by the physician.[17]
HF is among the major health issues resulting in increased morbidity and mortality. Sacubitril/valsartan is one of the newer drugs that found to be beneficial for lower EF patients. In addition to analyzing the prescription pattern for sacubitril/valsartan in HF patients exhibiting reduced EF, the current research sought to assess the medication’s effectiveness and tolerability in these patients.
In our study on comparison of biochemical and hemodynamic parameters, serum creatinine, serum potassium, systolic BP, and diastolic BP between baseline and after 5 months of follow-up, in serum creatinine (P = 0.06), no significant change was found, indicating that there is improvement in renal parameters. No significant statistical change in serum potassium (P = 0.380) was found. Systolic BP showed a slight decrease (P = 0.601), and diastolic BP showed a minimal and statistically insignificant change (P = 0.598). A statistically significant improvement in heart rate of patients (P = 0.027) was found. Sacubitril/valsartan leads to significant reverse cardiac remodeling (reduction in LV volumes and improvement in LVEF) within months, correlating with the clinical benefits.[18,19]
There was no change in serum creatinine level among the patients due to the influence of the combined effect of sacubitril/valsartan therapy. The afferent arteriolar dilation and decongestive effects of neprilysin inhibition counteract the efferent arteriolar dilation of valsartan, leading to GFR stability. This translates into a superior renal safety profile compared to traditional therapies, which is a significant advantage in managing HFrEF patients.[20,21]
Out of 50 study population, an increase in mild and moderate cases and a decrease in the severity of LV dysfunction, after 5 months of sacubitril/valsartan therapy, show clinical improvement in patients’ LV functioning. On considering the NYHA classification of patients according to severity grades (I–IV), the differences across time points were statistically significant (P = 0.005), reflecting improvement in the disease condition of several patients. The NYHA Classification system is used to grade the severity of HF symptoms. Patients are divided into four classes (I–IV) according to their physical activity limitations, ranging from no limitation (Class I) to symptoms even at rest (Class IV). There is a link between the drug’s neurohormonal action and structural cardiac improvement. Valsartan blocks angiotensin II type 1 receptors and reduces vasoconstriction, aldosterone, and fibrosis. Sacubitril inhibits neprilysin, which elevates the levels of natriuretic peptides (atrial natriuretic peptide and B-type natriuretic peptide) and would promote vasodilation, natriuresis, and anti-fibrosis. The combined therapy more effectively suppresses the neurohormonal drivers (angiotensin II, aldosterone, and endothelin) of pathological myocyte growth. Neprilysin inhibition increases cyclic guanosine monophosphate (cGMP) through natriuretic peptides. cGMP has downstream effects that may improve cardiomyocyte calcium cycling and reduce oxidative stress.[22]
Study limitations
The main limitation of the research was the short time period of the study. For knowing the long-term use of a drug, a study must be done in longer time period. Moreover, this observational study was done in a small sample size. Analyzing the precise effects of medication on HF patients with reduced EF requires a large sample size.
CONCLUSION
The study revealed the prescription pattern of sacubitril/valsartan in HF patients with reduced EF, which also helps in improvements of renal parameters. This study highlights that patients with reduced EF improved because of the blocking actions of sacubitril/valsartan. Also demonstrated, on beneficial therapy opting for managing patients with reduced EF because of its ability to reverse cardiac remodeling.
Authors’ contributions:
HS: Conceptualization; APP: Methodology, validation, investigation, data curation, writing - review & editing; SRS: Conceptualization, formal analysis.
Ethical approval:
The research/study was approved by the Institutional Review Board at Daya General Hospital Limited, number DH/ACADEMIC/DNB/07/25, dated 01st March 2025.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given consent for clinical information to be reported in the journal. The patient understands that the patient’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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