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      Angiotensin Receptor Neprilysin Inhibitors in HFrEF: Is This the First Disease Modifying Therapy Drug Class Leading to a Substantial Reduction in Diuretic Need?

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          Abstract

          Despite significant advances in disease modifying therapy in heart failure (HF), diuretics have remained the cornerstone of volume management in all HF phenotypes. Diuretics, alongside their definite acute haemodynamic and symptomatic benefits, also possess many possible deleterious side effects. Moreover, questions remain regarding the prognostic impact of chronic diuretic use. To date, few data exist pertaining to diuretic reduction as a result of individual traditional guideline directed medical therapy in HF with reduced ejection fraction (HFrEF). However, diuretic reduction has been demonstrated with sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor [ARNi]) from the PARADIGM study, as well as, post-marketing reports from our own group and others. Whether the ARNi compound represents the dawn of a new era, where effective therapies will have a more noticeable reduction on diuretic need, remains to be seen. The emergence of sodium glucose transport 2 inhibitors and guanylate cyclase stimulators may further exemplify this issue and potentially extend this benefit to HF patients outside of the HFrEF phenotype. In conclusion, emerging new therapies in HFrEF could reduce the reliance on diuretics in the management of this phenotype of HF. These developments further highlight the clinical importance to continually assess an individual's diuretic requirements through careful volume assessment.

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          Most cited references70

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          Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

          In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
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            Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

            Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).
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              Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

              We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
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                Author and article information

                Journal
                Int J Heart Fail
                Int J Heart Fail
                IJHF
                International Journal of Heart Failure
                Korean Society of Heart Failure
                2636-154X
                2636-1558
                April 2021
                25 February 2021
                : 3
                : 2
                : 106-116
                Affiliations
                [1 ]St. Vincent's University Hospital, Dublin, Ireland.
                [2 ]School of Medicine, University College Dublin, Dublin, Ireland.
                Author notes
                Correspondence to Brian Kerr, MB, BCh, MRCPI. St. Vincent's University Hospital, Merrion Road, Elm Park, Dublin D04 T6F4, Ireland. kerrbrian13@ 123456gmail.com
                Author information
                https://orcid.org/0000-0002-4071-8960
                https://orcid.org/0000-0001-5504-2978
                https://orcid.org/0000-0002-2095-603X
                https://orcid.org/0000-0002-5564-2890
                https://orcid.org/0000-0001-7391-2949
                https://orcid.org/0000-0001-8011-3301
                Article
                10.36628/ijhf.2020.0043
                9536695
                36262879
                dd34455b-e4d0-486d-8ae7-789691f5632f
                Copyright © 2021. Korean Society of Heart Failure

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 September 2020
                : 24 January 2021
                : 07 February 2021
                Categories
                Review Article

                diuretics,heart failure,systolic heart failure,angiotensin receptor antagonists,neprilysin

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