Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
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Dr Mohan Z Mani,
Professor & Head,
Department of Dermatolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
‘Knowledge is treasure of a wise man.’ The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help one’s reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journals–No manuscripts–No authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011
Anuradha

Dear team JCDR, I would like to thank you for the very professional and polite service provided by everyone at JCDR. While i have been in the field of writing and editing for sometime, this has been my first attempt in publishing a scientific paper.Thank you for hand-holding me through the process.


Dr. Anuradha
E-mail: anuradha2nittur@gmail.com
On Jan 2020

Important Notice

Original article / research
Year : 2022 | Month : April | Volume : 16 | Issue : 4 | Page : OC08 - OC13 Full Version

Benefits of Angiotensin Receptor-Neprilysin Inhibitor in Heart Failure with Reduced Ejection Fraction: A Longitudinal Study


Published: April 1, 2022 | DOI: https://doi.org/10.7860/JCDR/2022/54929.16200
Dharmendra Jain, Umesh Kumar Pandey, Suyash Tripathi, Abhishek Kaushley, Bhupendra Verma, Soumik Ghosh, Krishna Vemuri Santosh, Rajpal Prajapati

1. Professor, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 2. Assistant Professor, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 3. Assistant Professor, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 4. Senior Resident, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 5. Assistant Professor, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 6. Assistant Professor, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 7. Assistant Professor, Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India. 8. Assistant Professor, Department

Correspondence Address :
Umesh Kumar Pandey,
Flat-A3/11, Gopal Kunj Apartment, Naria, Varanasi-221005, Uttar Pradesh, India.
E-mail: pandeydrumesh@gmail.com

Abstract

Introduction: Combination of Angiotensin Receptor and Neprilysin Inhibitors (ARNI) has become the mainstay drug in treatment of Heart Failure (HF) with reduced Ejection Fraction (HFrEF). However, there are very few studies to evaluate the extent and spectrum of benefit of ARNI therapy in Indian HFrEF patients.

Aim: To observe the benefits of sacubitril/valsartan (ARNI) therapy on left ventricle function, parameters of cardiac remodelling, N terminal pro Brain-natriuretic peptide (NT-proBNP), rate of rehospitalisation for HF and detailed subgroup analysis in symptomatic HFrEF patients who are already receiving optimal medical therapy.

Materials and Methods: This longitudinal study was conducted at Cardiology Department of Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India, from September 2018 to August 2020. Total 200 patients of HFrEF with previous echocardiographic records of past six months, who did not show any further improvement in left ventricle dysfunction or cardiac dimensions were included in the study out of these 200 patients, 174 (87%) completed the one year follow-up. Patients were started on ARNI initially from 100 mg/day and up titrated to 400 mg/day. At each follow-up (6 weeks, 4 months, 6 months, 9 months and 1 year) clinical examination, New York Heart Association (NYHA) functional class, 2D Echocardiography and NT-ProBNP were done. Echocardiographic parameters of Cardiac Reverse Remodelling (CRR) i.e., Left Ventricular Ejection Fraction (LVEF), Left Ventricular End Diastolic Diameter (LVEDD), Left Ventricle End-Systolic Diameter (LVESD) were recorded at each follow-up. All categorical variables were shown in the form of frequency, mean with standard deviation and percentage.Intergroup comparison between different time periods was done by one-way Analysis of Variance (ANOVA) and paired t-test. A p-value <0.05 was considered statistically significant.

Results: Mean age of study population was 58.61±11.95 years, of whom 104 (59.77%) were males, and 70 (40.22%) were females. Mean LVEF increased from 30.42% at baseline to 45.98%, after 1 year (p-value <0.05). There was reduction in mean LVEDD of 4.5 mm (p<0.05) and LVESD of 3.86 mm (p-value <0.05) at 1 year. These benefits of CRR were observed in all the subgroups of study population (including diabetics, hypertensive, tobacco users, age, gender). Reduction in NT-ProBNP from 1097.65±769.7 pg/mL at baseline to 127.28 pg/mL after 1 year with mean reduction of 970.37±731.33 pg/mL (p-value <0.05). Rate of rehospitalisation for HF was 13.2% (N=23). A positive although weak correlation was seen between change in NT-ProBNP level and change in LVEF, LVEDD, LVESD as per Spearman’s rank correlation coefficient.

Conclusion: The ARNI was well tolerated in this Indian population as 72% achieved maximum dose of 400 mg. There was significant improvement in LV systolic function and cardiac dimensions and benefits extended to different subgroups of HFrEF patients along with positive although weak correlation between fall in NT-ProBNP level and improvement in LV function and cardiac dimensions over and above optimal medical therapy.

Keywords

Cardiac remodelling, Left ventricular dysfunction, N-terminal pro brain naturetic peptide, Sacubitril/valsartan

In this era of non communicable diseases, Heart Failure (HF) has emerged as a leading cause of mortality and morbidity. Chronic HF is a complex and progressive clinical syndrome resulting from any abnormality of cardiac structure or function. The prevalence of HF as well as rehospitalisation for HF are increasing, and the prognosis is poor with mortality within 5-years which is worse than many cancers (1),(2). Multiple recent advancement has been done in the arena of therapeutic management of HF. Combination of ARNI has established itself as a cornerstone evidence based drug in management of HF as per some recent landmark trials (3),(4). Neprilysin is a neutral endopeptidase, which degrades several endogenous vasoactive peptides including natriuretic peptides, bradykinin, and adrenomedullin (5),(6),(7). Due to inhibition of neprilysin, the level of these substances increases, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodelling (8),(9). Inhibition of both the renin-angiotensin system and neprilysin has effects that are superior to those of either approach alone in experimental studies (10),(11).

The PARADIGM-HF trial showed in comparison to enalapril, sacubitril/valsartan reduced the primary composite endpoint of cardiovascular death or HF hospitalisation by 20% (3). Although the physiological mechanisms of action of ARNI (sacubitril/valsartan) are well known, its effects on Left Ventricular Ejection Fraction (LVEF) and left ventricular dimensions have not been well studied in Indian population. In patients with Heart Failure with Reduced Ejection Fraction (HFrEF) left ventricular remodelling is a major mechanism underlying disease progression (12).

The primary aim of this study was to see the benefits of Angiotensin Receptor and Neprilysin Inhibitors (ARNI) over and above background optimum medical therapy on LV function and parameters of cardiac remodelling in Indian patients of HFrEF. The variables observed in each follow-up were echocardiographic parameters of Cardiac Reverse Remodelling (CRR) i.e., Left Ventricular Ejection Fraction (LVEF), Left Ventricular End Diastolic Diameter (LVEDD), Left Ventricle End-Systolic Diameter (LVESD) along with NT-pro BNP and rate of rehospitalisation for HF. Detailed subgroup analysis according to risk factors, age and gender in Indian patients of HFrEF was also done.

Material and Methods

This longitudinal study was done in Cardiology Department at Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, (tertiary care centre of north India) from September 2018 to August 2019 and patients were further followed-up for next one year (till August 2020). Ethical clearance was taken from the Institutional Ethics Committee (vide letter number EC/1419).

Sample size calculation: Estimated sample size was 158, assuming mean LVEF at baseline 25% and 34% at 3 months (13), keeping standard deviation of 0.4, α=0.05 and power=0.80.

Inclusion criteria: Patients of HFrEF with New York Heart Association (NYHA) class II-IV, age ≥18 years and LVEF of ≤40% who were symptomatic despite optimal medical therapy of HF {like ACE-I/ARB, beta blockers, Mineralocorticoid Receptor Antagonist (MRS), diuretics} and were required to have previous echocardiographic records of past 6 months who did not show any further improvement in LV dysfunction or cardiac dimensions were included in the study. Patients were required to have report of plasma NT pro BNP level >450 pg/mL along with stabilised Acute Decompensated Heart Failure (ADHF) patients admitted in Cardiac Care Unit (CCU). Patients suspected to have ischaemic aetiology have already undergone coronary angiography and revascularisation accordingly 3 months back before starting ARNI.

Exclusion criteria: Patients with symptomatic hypotension, a systolic blood pressure of less than 100 mmHg, estimated Glomerular Filtration Rate (e-GFR) below 30 mL/minute/1.73 m2 of body-surface area at screening or baseline serum creatinine ≥2 mg/dL, serum potassium >5.4 mmol/L or history of angioedema or unacceptable side-effect, hypersensitivity to sacubitril, valsartan, any ARBs, neprilysin inhibitors, or any of the sacubitril/valsartan excipients, presence of haemodynamically significant mitral and/or aortic valve disease except mitral regurgitation secondary to left ventricular dilatation, diagnosis of chemotherapy induced cardiomyopathy within the 12 months prior to admission were excluded.

Study Procedure

In case of prior history of Angiotensin Converting Enzyme inhibitor (ACE-I) intake, ACE-I was discontinued for a 36-hour washout period before starting sacubitril/valsartan. Although for ARB no such washout period was required and sacubitril/valsartan was given on the same day. Dose escalation (doubling of dose) was done to maximum permissible dose of 200 mg twice daily over a period of 4 weeks. Sacubitril/valsartan uptitration was done with the goal of achieving and maintaining sacubitril/valsartan 200 mg twice daily.

Patients with primary diagnosis of ADHF were stabilised before starting sacubitril/valsartan during hospitalisation. In these patients, haemodynamic stability was defined by maintenance of a systolic blood pressure of at least 100 mm Hg for the preceding 6 hours, with no increase in the dose of intravenous diuretics and no use of intravenous vasodilators during the preceding 6 hours and no use of intravenous inotropes during the preceding 24 hours.

These patients were followed for one year. The first visit was scheduled at two weeks after starting treatment with follow-up visits at 6 weeks, 4 months, 6 months, 9 months and 1 year. At each visit assessment of tolerability of sacubitril/valsartan was done. Transthoracic echocardiography was performed on Esaote 2D Echocardiography system with 3.5 MHz transducer. The Echocardiography analysis included the evaluation of LVEF, Left Ventricular End Systolic Dimension (LVESD) and Left Ventricular End Diastolic Dimension (LVEDD). NT-proBNP measurements was done at each visit. Primary outcome was improvement in LVEF and LV dimensions (systolic and diastolic) at the end of 1 year. Secondary outcome was improvement in NT-ProBNP level. Subgroup analysis was also done according to risk factors

Statistical Analysis

Statistical analysis was done using STATA software version 17.0. All continuous variables were shown in the form of mean with standard deviation and categorical variables in the form of frequency with 9percentage. The difference of NT-proBNP values from baseline to after one year of therapy was calculated and log transformation of square of this difference was done to make the normality of data. Data was analysed by using proper statistical test (parametric and non parametric). Intergroup comparison between different time periods was done by one-way Analysis of Variance (ANOVA) and paired t-test. A p-value <0.05 was considered statistically significant. Panel/longitudinal analysis was done with mean change in LVEF and log of square of NT-proBNP as panel data to assess changes in continuous echocardiography parameters between baseline and one year follow-up. Same statistical analysis was done for each subgroup of interest.

Results

Total of 200 patients were enrolled.Total 84 patients were enrolled from Inpatient Department (IPD) or CCU with diagnosis of acute decompensated HF, while rest of the patients (n=116) were enrolled from OPD with diagnosis of chronic compensated HF. Out of these 200 patients, 174 (87%) completed the one year follow-up. Data analysis was done for 174 patients as 14 patients died due to fatal arrhythmias and sudden cardiac death, eight patients were lost to follow-up and ARNI was discontinued in four patients due to adverse effects of drug (symptomatic hypotension in three, and worsening of renal function in one).

Mean age of study subjects were 58.61±11.95 years, of whom 104 (59.77%) were male and 70 (40.22%) were female. At the onset of study, majority of the patients were in NYHA class III 98 (56.32%). Ischaemic aetiology of HF was reported in 153 (87.93%), and others were of unknown aetiology (designated as idiopathic dilated cardiomyopathy). Total 59.7% (N=104) of study subjects had history of coronary revascularisation. Distribution of risk factor as shown in (Table/Fig 1) with 19 (10.9%) patients without any risk factor. At baseline mean±SD for LVEF was 30.42±5.12, for LVEDD was 60.57±3.12 mm and for LVESD was 46.56±4.03 mm. Atrial fibrillation was seen in 11 (6.32%) patients. Maximum dose of ARNI 400 mg/day was achieved by 125 (71.8%), 200 mg/day in 44 (25.3%) and 100 mg/day in 5 (2.3%) patients.

Background medical treatment consisted of beta-blocker, ACE-I/ARB, mineralocorticoid receptor antagonist and diuretics (Table/Fig 1), along with optimal medical therapy for coronary artery disease in ischaemic aetiology

Benefits in LV systolic function: There was significant improvement in mean difference of ejection fraction from baseline to one year 15.56±6.82 (95% CI 14.55-16.59, p-value <0.05). Mean of LVEF increased sequentially from baseline value of 30.42±5.12 to 31.52±5.78 (p-value <0.05) at six weeks, with major difference in absolute mean value from baseline was found at 4 months (30.42±5.10 vs. 37.17±7.16, p-value <0.05) and further at 6 months 41.97±7.18 (p-value <0.05), at 9 months 44.48±7.1 (p-value <0.05) and in one year 45.98±6.96 (p-value <0.05). Panel/longitudinal data analysis shows improvement in LVEF at each visit with maximum benefits started to appear after four months of therapy (Table/Fig 2)a.

There was significant improvement in mean LVEF from baseline to one year across all the spectrum of risk factors (Table/Fig 2)b the mean increase in LVEF across all the risk factor ranges from 14.37-17.81%, maximum absolute increase in mean LVEF was seen with tobacco+Hypertension subgroup but on applying one way ANOVA test between the mean increase in LVEF among all risk factors, no statistical significance was found, thereby implying that benefits of ARNI are independent of risk factors. Gender based analysis showed similar benifit among male and female with mean increase in LVEF of 15.54% in males and 15.61% in females.

Age was divided into quantile subgroups and analysis was done which showed maximum improvement in LVEF in 1st quantile of 18.16±6.9% and minimum benefits of 13±7.0% in 4th quantile (Table/Fig 2)c. On applying one-way ANOVA test between 1st and 4th quantile it was found to be statistically significant with p-value <0.05 which implies that maximum beneifit of ARNI therapy was seen with 1st quantile which corresponds to younger age group. Comparison of improvement in LVEF in atrial fibrillation versus sinus rhythm group was also done. Change in ejection fraction from baseline to one year was significant in both atrial fibrillation and sinus rhythm group, however, the mean change was only 10% (95% CI: 5.5-14.5, p-value <0.05) in atrial fibrillation subgroup, while it was 15.95% (95% CI: 14.9-16.99, p-value <0.05) in sinus rhythm group (Table/Fig 2)d.

Subgroup analysis of improvement in LVEF with ARNI therapy was done according to diffrent risk factors, age quantiles and gender which showed that benefits with ARNI therapy was across all the subgroups (Table/Fig 3).

Benefits in cardiac dimensions: The mean LVEDD at baseline was 60.57±3.12 mm and 56.03±3.16 mm at the end of one year. There was significant decrease in mean LVEDD of 4.5±1.1 mm (95% CI: 5.1-3.8, p-value <0.05) after one year of therapy. Subgroup analysis showed benefit across all subgroups as shown in (Table/Fig 4).

The mean LVESD at baseline was 46.56±4.03 mm versus 42.90±4.1 mm at 12 months. There was statistically significant reduction in mean of LVESD of 3.66±1.1 mm (95% CI: 3.82-3.49,
p-value <0.05) after one year of therapy. Sub group analysis shows statistically significant improvement in cardiac dimensions in all the subgroups as shown in (Table/Fig 5).

Rehospitalisation: Total of 23 patient required rehospitalisation for HF. Rate of rehospitalisation for HF was 13.2%.

Reduction in NT-proBN P levels: Mean NT proBNP level at base line was 1097.65 pg/mL and after 12 months of ARNI therapy was 127.28 pg/mL. There was significant reduction in mean of NT-proBNP 970.37±731.33 pg/mL (95% CI: 1086.13-854.60, p-value <0.05). Panel/longitudnal analysis [Table/Fig-6a] shows decrease in NT-proBNP level with each visit with maximum absolute reduction occuring after 6 weeks of therapy 535.03±61.49 pg/mL (95% CI: 655.98-404.08, p-value <0.05)

NT-proBNP data was transformed for the purpose of normalisation by taking log of square of NT-proBNP and compared with change in mean LVEF, LVEDD and LVESD. Spearman’s rank correlation coefficient was calculated to find any association between reduction in NT-proBNP level with change in LVEF, LVEDD, LVESD. Positive although weak correlation was found between mean change in NT-proBNP and change in LVEF, LVEDD, LVESD as shown in (Table/Fig 6)b-d.

Discussion

Patients with HF have an estimated 5 year mortality of 59% as per Trivandrum HF registry (14). For the past 25 years, an add-on therapy approach to chronic HF has been used, beginning with diuretics, then adding ACE inhibitors (or ARBs) and beta blockers, followed by mineralocorticoid receptor antagonists (15),(16),(17). Ivabradine, which reduces heart rate, is also approved as an add-on therapy in HF (18). Nevertheless, morbidity and mortality remain high, therefore there was an unmet need for new therapeutic targets in HF. Following the disappointing outcomes of combined ACE-I/neprilysin inhibition, the combination of an ARB and neprilysin inhibitor was investigated.

In the present study, the major aetiology of HFrEF was ischaemic heart disease, which was found in 153 (87.93%) subjects. In the study done by Balmforth C et al., an analysis of PARADIGM-HF outcomes and effect of treatment according to aetiology in HFrEF demonstrated that among the 8,399 patients randomised, 5,036 (60.0%) had an ischaemic aetiology (19). Gheorghiade M et al.,in a review of 24 trials published between 1986 and 2005, reported that 62% of patients had an investigator-reported ischaemic aetiology and in more recent trials the proportion has varied between 65%-70% in studies with a high proportion of European patients (especially from Central/Eastern Europe) to 56% in another large global trial with significant numbers of patients from Asia and Latin America (3),(18),(20),(21),(22).

In the present study, ARNI lead to significant improvement in LVEF of about 15% along with significant reduction in LVESD of 3.6 mm and LVEDD of 4.5 mm after one year of therapy. Almufleh A et al., demonstrated Sacubitril/Valsartan use was associated with an average 5% (±1.2) increase in EF, from a mean baseline of 25.33% to 30.14% (p-value <0.001) with a median duration of treatment 3 months (13). They concluded sacubitril/valsartan was found to improve EF and multiple measures of reverse cardiac remodelling beyond the effects of concomitant optimal medical therapy. Gonzalez-Torres L et al.,observed that after 3 months of therapy with ACEI/ARB, there was an initial increase of LVEF, maintaining constant values along time from 3-9 months after that when ARNI was started, further significant increase of LVEF was observed (23). Therapy with ARNI increased LVEF from 31±6-36.5±8%, (p-value <0.002) and decreased LVEDD from 62±6-60±6 mm, (p-value <0.02) and significantly decreased Left Ventricular End-Diastolic Volume (LVEDV) from 141±17 mm to 119±15 mm (p-value <0.01). The major finding of this study is that sacubitril/valsartan was able to reverse the cardiac remodelling, in the form of
increasing LVEF by 5-6% and decreasing LV size. Additionally, treatment with sacubitril/valsartan was correlated to a significant improvement of NYHA functional class.

Martens P et al.,conducted a prospective study which included 125 HFrEF patients (66±10 years) with a median (IQR) follow-up of 118 (77-160) days after initiation of sacubitril/valsartan has shown significant LVEF improvement (29.6±6% vs 34.8±6%; p-value <0.001) and reduction in Left Ventricular End Systolic (LVESV) and LVEDV which was statistically significant (24). A dose-dependent effect was noted for changes in LVEF (p-value <0.001) and LVESV (p-value=0.031), with higher doses of sacubitril/valsartan leading to more reverse remodelling. They concluded switching therapy in eligible HFrEF patients from a RAS-blocker to sacubitril/valsartan induces beneficial reverse remodelling of both metrics of systolic as well as diastolic function. Wang Y et al.,conducted a meta-analysis to compare the effects of ARNI versus angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on CRR indices (25). They searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Twenty studies enrolling 10175 patients were included. Angiotensin receptor and neprilysin inhibitors outperformed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. Improvements in CRR indices were observed at 3 months and became more significant with longer follow-up to 12 months. They concluded ARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin-converting enzyme inhibitors/
angiotensin receptor blockers in HF with reduced EF patients, even after short-term follow-up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as after 3 months of therapy. The benefits of ARNI were manifest at 3 months and lasted for 12 months.

In the present study, the significant benefit of ARNI started at 6 weeks and continued for 1 year but major change in absolute mean value of LVEF seen at 4 months of ARNI therapy, more importantly different subgroup analysis done in present study showed that benefit of ARNI therapy extends across all the risk factors, age groups and gender. The rate of rehospitalisation for HF in present study was 13.2% which is comparable to first rehospitalisation due to HF seen in paradigm HF trial (12.8%) (10). In PROVE HF trial, reduction in NT-proBNP level correlation with improvement in marker of cardiac volume and LVEF was studied (4). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF. At 12 months, LVEF increased from 28.2-37.8%, while LVEDVI decreased from 86.93-74.15 mL/m2. In the present study also, a positive although weak correlation was seen in change in NT-proBNP level and improvement in LV function and cardiac dimensions.

The benefits, in terms of improvement in LVEF and cardiac dimension, in the present study are attributed to ARNI therapy as it was prescribed in HFrEF patients symptomatic despite on optimal medical therapy and the pervious echocardiographic records of past 6 months didn’t showed any further improvement in LV function or cardiac dimensions. It is known from the earlier studies that beta blockers improve LVEF by 4-12% (26), ACEI/ARB improve LVEF between 1-4% (27),(28),(29), and MRA by another 4% (28). In the present study, additional benefit in LVEF of approximately 15% and reduction in cardiac dimensions, a marker of CRR were seen only after switching therapy from ACEI/ARB to ARNI over and above other standard drug therapy for HFrEF.

An observational study was performed and the sample size of the studied group was limited. The single-centre study design may affect the generalisability of results. Large randomised controlled trials are needed in Indian subset with special emphasis on multicentre clinical experience and strong follow-up data.

Conclusion

Angiotensin receptor and neprilysin inhibitors (sacubitril/valsartan) was found to improve LVEF and left ventricular dimensions (LVESD, LVEDD) in symptomatic HFrEF patients over and above optimal medical therapy used in management. A favourable response to ARNI starts at 6 weeks with maximum benefit being manifested at 4 months and consistent up to one year. Benefits extend to all subgroups of HF patients and there was also reduction in rate of rehospitalisation for HF. Admitted patients with ADHF after stabilisation and chronic HFrEF were benefited with early initiation of ARNI.

References

1.
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics 2015 update: A report from the American Heart Association. Circulation. 2015;131:e29-322.
2.
Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More “malignant” than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3:315-32. [crossref]
3.
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. [crossref] [PubMed]
4.
Januzzi Jr JL, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, et al. Association of change in NT-proBNP after starting sacubitril-valsartan with cardiac structure and function in HFrEF. JAMA. 2019;322(11):1085-95. [crossref] [PubMed]
5.
Cruden NL, Fox KA, Ludlam CA,Johnston NR, Newby DE. Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. Hypertension. 2004;44:913-18. [crossref] [PubMed]
6.
Rademaker MT, Charles CJ, Espiner EA,Nicholls MG, Richards AM, Kosoglou T. Neutral endopeptidase inhibition: Augmented atrial and brain natriuretic peptide, haemodynamic and natriuretic responses in ovine heart failure. Clin Sci (Lond). 1996;91:283-91. [crossref] [PubMed]
7.
Wilkinson IB, McEniery CM, Bongaerts KH, MacCallum H, Webb DJ, Cockcroft JR. Adrenomedullin (ADM) in the human forearm vascular bed: Effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP). Br J Clin Pharmacol. 2001;52:159-64. [crossref] [PubMed]
8.
Maric C, Zheng W, Walther T. Interactions between angiotensin ll and atrial natriuretic peptide in renomedullary interstitial cells: The role of neutral endopeptidase. Nephron Physiol. 2006;103:149-56. [crossref] [PubMed]
9.
Kuhn M. Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol. 2004;99:76-82. [crossref] [PubMed]
10.
Rademaker MT, Charles CJ, Espiner EA,Nicholls MG, Richards AM, Kosoglou T. Combined neutral endopeptidase and angiotensin-converting enzyme inhibition in heart failure: Role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol. 1998;31:116-25. [crossref] [PubMed]
11.
Trippodo NC, Fox M, Monticello TM, Panchal BC, Asaad MM. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol. 1999;34:782-90. [crossref] [PubMed]
12.
Vasan RS, Larson MG, Benjamin EJ, Evans JC, Levy D. Left ventricular dilatation and the risk of congestive heart failure in people without myocardial infarction. N Engl J Med. 1997;336:1350-55. [crossref] [PubMed]
13.
Almufleh A, Marbach J, Chih S, Stadnick E, Davies R, Liu P, et al. Ejection fraction improvement and reverse remodeling achieved with Sacubitril/Valsartan in heart failure with reduced ejection fraction patients. Am J Cardiovasc Dis. 2017;7(6):108-13.
14.
Harikrishnan S, Jeemon P, Ganapathi S, Agarwal A, Viswanathan S, Sreedharan M, et al. Five-year mortality and readmission rates in patients with heart failure in India: Results from the Trivandrum heart failure registry. International Journal of Cardiology. 2021;326:139-43. [crossref] [PubMed]
15.
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-07. [crossref]
16.
Sliwa K, Norton GR, Kone N, Candy G, Kachope J, Woodiwiss AJ, et al. Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure. J Am Coll Cardiol. 2004;44:1825-30. [crossref] [PubMed]
17.
McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet. 2003;362:767-71. [crossref]
18.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet. 2010;376:875-85. [crossref]
19.
Balmforth C, Simpson J, Shen L, Jhund PS, Lefkowitz M, Rizkala AR, et al. An analysis of PARADIGM-HF outcomes and effect of treatment according to etiology in HFrEF. JACC Heart Failure. 2019;7(6):457-65. [crossref] [PubMed]
20.
Gheorghiade M, Sopko G, De Luca L, Velazquez EJ, Parker JD, Binkley PF, et al. Navigating the crossroads of coronary artery disease and heart failure. Circulation. 2006;114:1202-13. [crossref] [PubMed]
21.
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. The EMPHASIS-HF Study Group. N Engl J Med. 2011;364:11-21. [crossref] [PubMed]
22.
McMurray JJ, Krum H, Abraham WT, Dickstein K, Køber LV, Desai AS, et al. Aliskiren, enalapril, or aliskiren and enalaprilinheart failure. N Engl J Med. 2016;374:1521-32. [crossref] [PubMed]
23.
Gonzalez-Torres L, De Diego C, Centurion R, Macias M, De Lara G, Carrasco R, et al. Angiotensin-neprilysin inhibition further reverses cardiac remodeling as compared to angiotensin inhibition in reduced heart failure patients. Clin Cardiol J. 2018;2(1):06-09.
24.
Martens P, Beliën H, Dupont M, Vandervoort P, Mullens W. The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovascular Therapeutics. 2018;36(4):e12435. [crossref] [PubMed]
25.
Wang Y, Zhou R, Lu C, Chen Q, Xu T, Li D, et al. Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis. J Am Heart Assoc. 2019;8(13):e012272. [crossref] [PubMed]
26.
Suematsu Y, Miura S, Goto M, Matsuo Y, Arimura T, Kuwano T, et al. LCZ696, an angiotensin receptor-neprilysinn inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice. Eur J Heart Fail. 2016;18:386e393. [crossref] [PubMed]
27.
Gotzsche CO, Sogaard P, Ravkilde J, Thygesen K. Effects of captopril on left ventricular systolic and diastolic function after acute myocardial infarction. Am J Cardiol. 1992;70:156-60. [crossref]
28.
Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation. 1996;94:2800-06. [crossref] [PubMed]
29.
Chan AK, Sanderson JE, Wang T, Lam W, Yip G, Wang M, et al. Aldosterone receptor antagonism induces reverse remodeling when added to angiotensin receptor blockade in chronic heart failure. J Am Coll Cardiol. 2007;50:591-96. [crossref] [PubMed]

DOI and Others

DOI: 10.7860/JCDR/2022/54929.16200

Date of Submission: Jan 13, 2022
Date of Peer Review: Jan 25, 2022
Date of Acceptance: Feb 21, 2022
Date of Publishing: Apr 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

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