Carta Acesso aberto Revisado por pares

Oral Milrinone for the Treatment of Chronic Severe Right Ventricular Failure in Left Ventricular Assist Device Patients

2021; Lippincott Williams & Wilkins; Volume: 14; Issue: 4 Linguagem: Inglês

10.1161/circheartfailure.120.007286

ISSN

1941-3297

Autores

Nir Uriel, Daniel Burkhoff, Gene Kim, Tracey Silverstein, C. Juricek, David M. Kaye, Gabriel Sayer,

Tópico(s)

Heart Failure Treatment and Management

Resumo

HomeCirculation: Heart FailureVol. 14, No. 4Oral Milrinone for the Treatment of Chronic Severe Right Ventricular Failure in Left Ventricular Assist Device Patients Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBOral Milrinone for the Treatment of Chronic Severe Right Ventricular Failure in Left Ventricular Assist Device Patients Nir Uriel, MD, MSc, Daniel Burkhoff, MD, PhD, Gene Kim, MD, Tracey Silverstein, BSN, RN, Colleen Juricek, APN, David M. Kaye, MD, PhD and Gabriel Sayer, MD Nir UrielNir Uriel Correspondence to: Nir Uriel, MD, MSc, Division of Cardiology, Columbia University Irving Medical Center, 622 W 168th St, PH 4-129, New York, NY 10032. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2301-3587 Division of Cardiology, Columbia University Irving Medical Center, New York, NY (N.U., D.B., G.S.). , Daniel BurkhoffDaniel Burkhoff https://orcid.org/0000-0003-3995-2466 Division of Cardiology, Columbia University Irving Medical Center, New York, NY (N.U., D.B., G.S.). , Gene KimGene Kim Section of Cardiology (G.K., T.S.), University of Chicago Medicine, IL. , Tracey SilversteinTracey Silverstein Section of Cardiology (G.K., T.S.), University of Chicago Medicine, IL. , Colleen JuricekColleen Juricek Department of Surgery (C.J.), University of Chicago Medicine, IL. , David M. KayeDavid M. Kaye https://orcid.org/0000-0003-4058-0372 Department of Cardiology, Alfred Hospital, Melbourne, Australia (D.M.K.). and Gabriel SayerGabriel Sayer https://orcid.org/0000-0003-1701-1593 Division of Cardiology, Columbia University Irving Medical Center, New York, NY (N.U., D.B., G.S.). Originally published19 Mar 2021https://doi.org/10.1161/CIRCHEARTFAILURE.120.007286Circulation: Heart Failure. 2021;14:e007286Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 19, 2021: Ahead of Print Left ventricular assist devices (LVADs) are effective for circulatory support both as a bridge to transplantation and as destination therapy. However, right ventricular failure (RVF) remains a significant acute and chronic problem following LVAD implantation. Current therapies for acute RVF include intravenous inotropes and RV assist devices, both of which are typically weaned during the index admission. Chronic RVF is often managed by adjustment of LVAD speed and medications. In selected cases of persistent RVF, patients can be treated with chronic intravenous inotropic therapy.1 However, the use of home inotropic therapy is complicated by the risk of infection due to the indwelling venous catheter. Milrinone, a phosphodiesterase-3 inhibitor, enhances cardiac contractility by increasing intracellular levels of cAMP. The intravenous formulation of the medication is widely used in the treatment of advanced heart failure, but previous attempts to develop an oral version of this medication led to excess mortality in treated patients.2,3 CRD-102 (Cardiora, Melbourne, Australia) is a novel, orally administered extended release formulation of milrinone.4 Here, we present our experience with CRD-102 in LVAD patients with chronic RVF.The data that support the findings of this study are available from the corresponding author upon reasonable request. This was a single-center, open-label, single-arm study designed to evaluate the safety and tolerability of CRD-102 (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03217331). The study protocol was approved by the University of Chicago Institutional Review Board, and all patients provided informed consent. We enrolled stable LVAD patients who were at least 30 days postimplantation, had a functioning implantable cardioverter-defibrillator (ICD), RV dysfunction on echocardiography as well elevated right atrial pressure despite diuretic therapy. Patients with mean arterial pressure >95 mm Hg, glomerular filtration rate <25 mL/min per 1.73 m2 or those with ventricular tachycardia in preceding 30 days were excluded. All patients underwent right heart catheterization with documentation of right atrial pressure ≥12 mm Hg before initiating therapy. CRD-102 was administered at a dose of 14 mg twice daily for 2 weeks. All comparisons between baseline measurements and end-of-study measurements were made using paired t tests.Among 13 patients screened for the study, 5 were excluded due to right atrial pressure <12 mm Hg during right heart catheterization, and one was excluded due to persistent hypokalemia. Six patients were enrolled; median age was 62.5 years, 4 were male, 3 had ischemic cardiomyopathy. One patient was withdrawn from the study after 4 days on treatment due to ventricular fibrillation that was successfully treated with an ICD shock. At the time of the ICD shock, the patient's potassium level was 2.9 meq/L. There were no other serious adverse events in the study. No arrhythmias were detected by ICD interrogation in the other study patients.Hemodynamic parameters before oral milrinone and during therapy are shown in the Figure. Right atrial pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure did not change significantly. However, cardiac output improved from 3.9±0.6 to 5.8±1.9 L/min (P=0.036) and, consequently, pulmonary vascular resistance and systemic vascular resistance both decreased significantly. RV stroke work index also improved from 4.0±1.1 to 5.4±1.7 g/m2 per beat (P=0.04). Left ventricular ejection fraction, tricuspid annular plane systolic excursion, and the geometric mean of N-terminal pro-B-type natriuretic peptide did not change significantly, while creatinine level increased from 1.5±0.5 to 1.7±0.4 mg/dL (P=0.011). The aortic valve did not open in any of the patients either before or during therapy with oral milrinone. Kansas City Cardiomyopathy Questionnaire summary score improved significantly from 52±21 to 65±19 (P=0.041).Download figureDownload PowerPointFigure. Changes in hemodynamic parameters from beginning of study (pretreatment) to end of treatment period (on-treatment). Individual patients are depicted by the colored lines. The black lines represent averages for the group. The mean change is indicated below each graph along with the 95% CI. PA indicates pulmonary artery; PCWP, pulmonary capillary wedge pressure; and RVSWI, right ventricular stroke work index.RVF during LVAD support remains a significant problem that increases both morbidity and mortality. While acute RVF following LVAD implantation can be treated with a temporary RV assist device, the management of severe chronic RVF is challenging due to limited use of durable RV assist devices. In addition to overt cases, many patients with LVAD suffer from more subtle forms of RVF. In a hemodynamic study of stable LVAD outpatients, ≈40% had elevated central venous pressure, suggesting a significant degree of right heart dysfunction.5 In these patients, exercise tolerance may be limited due to poor RV response to activity. A significant unmet need exists to develop therapeutic options for these patients.Prior studies of oral milrinone demonstrated an increase in arrhythmias and mortality in patients with chronic heart failure but were conducted before the modern era of treatment, including β-blockers and ICDs.2,3 In our study, there was one episode of serious arrhythmia, which occurred in the context of severe hypokalemia. This patient was protected by a properly functioning ICD and did not experience any other significant consequences. All study patients experienced an increase in cardiac output and RV stroke work index as anticipated by the mechanism of action of CRD-102. The lack of change in intracardiac filling pressures may have been due to the short study period and the absence of prespecified diuretic protocols. However, all patients experienced a reduction in pulmonary vascular resistance, which might translate into improved RV function with a longer duration of therapy. Subjective reports of marked improvement in symptoms were confirmed by the significant increase in Kansas City Cardiomyopathy Questionnaire scores. Admittedly, these improvements may have been due to a placebo effect in this open-label study, but in concert with the documented improvements in cardiac output, pulmonary vascular resistance, and RV stroke work index, they are supportive of further study of oral milrinone in LVAD patients with RVF. This study is a proof of concept of the safety of CRD-102, and the efficacy of this medication should be tested in a larger randomized study.Nonstandard Abbreviations and AcronymsICDimplantable cardioverter-defibrillatorLVADleft ventricular assist deviceRVFright ventricular failureSources of FundingThis study was funded by a grant from Cardiora Pty Ltd. Cardiora did not participate in data collection, data analysis, or article preparation.Disclosures Dr Kaye is the cofounder of Cardiora Pty Ltd and coinventor of CRD-102. Dr Sayer has received consulting fees from Abbott Laboratories. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page 506.Correspondence to: Nir Uriel, MD, MSc, Division of Cardiology, Columbia University Irving Medical Center, 622 W 168th St, PH 4-129, New York, NY 10032. Email [email protected]columbia.eduReferences1. Anyanwu EC, Kagan V, Bhatia A, Tehrani DM, Adatya S, Kim G, Sarswat N, Jeevanandam V, Sayer G, Uriel N. Home inotropes in patients supported with left ventricular assist devices.ASAIO J. 2019; 65:e7–e11. doi: 10.1097/MAT.0000000000000753CrossrefMedlineGoogle Scholar2. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.N Engl J Med. 1991; 325:1468–1475. doi: 10.1056/NEJM199111213252103CrossrefMedlineGoogle Scholar3. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, Gottlieb SO, McGrew F, DeMets DL, White BG. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.N Engl J Med. 1998; 339:1810–1816. doi: 10.1056/NEJM199812173392503CrossrefMedlineGoogle Scholar4. Nanayakkara S, Mak V, Crannitch K, Byrne M, Kaye DM. Extended release oral milrinone, CRD-102, for advanced heart failure.Am J Cardiol. 2018; 122:1017–1020. doi: 10.1016/j.amjcard.2018.06.009CrossrefMedlineGoogle Scholar5. Uriel N, Sayer G, Addetia K, Fedson S, Kim GH, Rodgers D, Kruse E, Collins K, Adatya S, Sarswat N, et al. Hemodynamic ramp tests in patients with left ventricular assist devices.JACC Heart Fail. 2016; 4:208–217. doi: 10.1016/j.jchf.2015.10.001CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Vishram-Nielsen J, Tomasoni D, Gustafsson F and Metra M (2022) Contemporary Drug Treatment of Advanced Heart Failure with Reduced Ejection Fraction, Drugs, 10.1007/s40265-021-01666-z, 82:4, (375-405), Online publication date: 1-Mar-2022. Wang T, Cevasco M, Birati E and Mazurek J (2022) Predicting, Recognizing, and Treating Right Heart Failure in Patients Undergoing Durable LVAD Therapy, Journal of Clinical Medicine, 10.3390/jcm11112984, 11:11, (2984) April 2021Vol 14, Issue 4 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.120.007286PMID: 33736460 Originally publishedMarch 19, 2021 Keywordshemodynamicsheart failuremilrinoneechocardiographyPDF download Advertisement SubjectsClinical StudiesHeart Failure

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