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Congestive Heart Failure
Published in Stephen M. Cohn, Alan Lisbon, Stephen Heard, 50 Landmark Papers, 2021
Brooks Willar, E. Wilson Grandin
Providers need to consider a few important clinical factors when initiating inpatient ARNI therapy. A 36-hour washout period from ACEi is needed prior to starting ARNI due to the significant risk of angioedema with concomitant ACE and neprilysin inhibition, both of which can potentiate bradykinin levels. For patients admitted with decompensated heart failure, particularly those who require the ICU for low cardiac output, this 36-hour washout without any ACEi/ARB/ARNI therapy should be avoided as withdrawal of that afterload reduction can be highly detrimental in these vulnerable patients. A sensible approach for patients with marginal blood pressure is starting a low-dose ARB, which, if tolerated, can be transitioned to low-dose sacubitril-valsartan (24–26 mg). The ionic form of valsartan found in sacubitril-valsartan is 40% more bioavailable than the salt used in stand-alone valsartan, so 26 mg of valsartan in sacubitril-valsartan is roughly equivalent to 40 mg of traditional valsartan [9]. For patients with marginal blood pressure, we suggest initiating valsartan at 20 mg twice daily and uptitrating to 40 mg twice daily before transitioning to low-dose sacubitril-valsartan. When titrating ARNI therapy in patients with marginal blood pressure, allow 48–72 hours at a stable dose before considering an increase to the next dosing level.
Pathophysiology of Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Jacob Cao, John O'Sullivan, Sean Lal
Based on their physiological mechanisms, multiple natriuretic peptide analogues and endopeptidase inhibitors have progressed through preclinical studies to human trials. Nesiritide, a recombinant BNP, although showing hemodynamic benefits in earlier studies, did not reduce death or rehospitalization compared to placebo in a large long-term trial. Neprilysin is a membrane-bound metalloproteinase that cleaves and inactivates various peptide hormones, including natriuretic peptides, bradykinin, substance P, and beta amyloids. Early neprilysin inhibitors were shown to promote natriuresis, but the effect was not sustained, likely because AT II breakdown was also inhibited. Consequently, dual blockade of neprilysin and ACE was thought to be the solution. The neprilysin-ACE inhibitor omapatrilat was compared with ACE inhibitor alone in the phase III trial OVERTURE,4 showing no reduction in the composite primary endpoint of all-cause mortality and HF hospitalization, but causing a reduction in the secondary endpoint of all-cause mortality and cardiovascular hospitalization. However, on account of the unacceptable rise in the angioedema rate in the treatment group, related to omapatrilat inhibition of bradykinin breakdown, further development of this agent was ceased. The more recently developed agent sacubitril-valsartan carries the dual advantage that sacubitrilat (active metabolite of sacubitril) does not inhibit aminopeptidase P, which breaks down bradykinin, and that valsartan does not inhibit ACE, which also contributes to bradykinin inactivation (Figure 3.2). Accordingly, sacubitril-valsartan was compared with enalapril for HFrEF patients in the recent phase III trial PARADIGM-HF,5 demonstrating the marked superiority of sacubitril-valsartan in terms of all-cause mortality, cardiovascular mortality, and HF hospitalization, with a non-significant rise in non-serious angioedema. Replacing ACE inhibitor or ARB with sacubitril-valsartan now holds a level I class of recommendation in all major international guidelines for HFrEF.6,7Sacubitril-valsartan mechanism of action in heart failure. (Reproduced with permission from: Vardeny, Miller, and Solomon, JACC Heart Fail 2014;2:663–70.)
Safety and efficacy considerations amongst the elderly population in the updated treatment of heart failure: a review
Published in Expert Review of Cardiovascular Therapy, 2022
In addition, two trials were performed amongst those patients with heart failure while taking sacubitril/valsartan to further define benefits. The first study was titled the EVALUATE-HF trial, average age of 67.3 years old, which aimed to determine if the ARNI aids in aortic stiffness and cardiac remodeling when compared to enalapril [19]. Again, study details are provided in Table 2. The study concluded that there was no difference in, measuring aortic characteristic impedance (Zc), between the two classes of medications, but encourages conceptualizing further mechanisms providing heart failure aid [19]. Another trial, PROVE-HF trial, determined there was an LVEF increase in those patients with HFrEF taking the ARNI [20]. In this trial, the average age was 65.1 years old, and the investigators saw an increase of ejection fraction from 28.2% to 37.8%, a 9.4% increase (95% CI 8.8 to 9.9, p < 0.001) [20]. Thus, these trials underscore the efficacy of the ARNI in those patients ≥65 years old, as well as offering some evidence in those ≥75 years old.
Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction
Published in Expert Opinion on Pharmacotherapy, 2022
Emanuel Raschi, Igor Diemberger, Mario Sabatino, Elisabetta Poluzzi, Fabrizio De Ponti, Luciano Potena
A recent systematic review meta-analyzed data from 20 RCTs to assess the safety and tolerability of sacubitril/valsartan compared with standard of care or placebo, across all conditions and settings [65]. Overall, sacubitril/valsartan was at least as safe and tolerable as the standard therapy in terms of serious adverse events, discontinuation for adverse events and adverse events of special interest, namely angioedema, cough, hyperkalemia, hypotension, and acute kidney injury. There was a 45% increased risk of hypotension with sacubitril/valsartan compared with active controls, especially from trials in patients with HF and long follow-up periods, and a higher risk of angioedema in follow-ups longer than 12 months (event rate 0.49% vs 0.20%). Although almost all the angioedema events were mild episodes, without airway compromise, a selection bias cannot be ruled out considering that patients with a history of angioedema or angioedema during the active run-in were excluded. Therefore, due to limitations of this pooled study-level meta-analysis, including heterogeneity of trials and individual studies as well as the inability to assess long-term safety concerns, observational studies and pharmacovigilance are pivotal to fully characterize these unsettled issues in the real world.
Determinants of maximal dose titration of sacubitril/valsartan in clinical practice
Published in Acta Cardiologica, 2021
Pieter Martens, Lina Verluyten, Heleen Van de Broek, Frauke Somers, Jeroen Dauw, Matthias Dupont, Wilfried Mullens
Although real-world data is starting to emerge on the use of sacubitril/valsartan in clinical practice, limited data is available about the doses actually being used in heart failure. Recently, a German cohort study assessing pharmacy prescriptions in 26,191 patients indicated that in the entire cohort, 21% of patients were being treated with the maximal dose [10]. Our data further extents this data, indicating that in our entire cohort around 26% of patients were able to tolerate the maximal dose after uptitration. Moreover, in a sensitivity analysis restricted to patients who had multiple (≥2) follow-ups in the heart failure clinic, the proportion of patients on a maximal dose further increased to 32%. These proportions of patients on target dose for sacubitril/valsartan are strikingly better, than the low proportion (2%) of patients on target dose for sacubitril/valsartan in the CHAMP-HF registry performed in the USA [6,7]. Both our data and the recent German study, indicate that most patients are initiated on the lowest dose of sacubitril/valsartan, which is not in line with the Summary of Product Characteristics of sacubitril/valsartan, suggesting the intermediate dose of 49/51 mg twice daily as the preferred starting dose. In clinical practice patients are older, more frail and have extensive comorbidities, including chronic renal disease which might mandate some caution and lead to lower starting doses [3]. Nevertheless, in a heart failure clinic with dedicated protocol driven uptitration, a majority of patients will be able to receive uptitration.