European Journal of Heart Failure (2022) 24, 750–761 REVIEW doi:10.1002/ejhf.2503 Practical outpatient management of worsening chronic heart failure Nicolas Girerd1* , Nathan Mewton2, Jean-Michel Tartière3, Damien Guijarro4, Patrick Jourdain5,6, Thibaud Damy7, Nicolas Lamblin8, Antoni Bayes-Génis9, Pierpaolo Pellicori10, James L. Januzzi11, Patrick Rossignol1, and François Roubille12, on behalf of a panel of multidisciplinary experts and the Heart Failure Working Group of the French Society of Cardiology 1 Centre d’Investigation Clinique- Plurithématique Inserm CIC-P 1433, Inserm U1116, CHRU Nancy Brabois, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Université de Lorraine, Nancy, France; 2 Hôpital Cardiovasculaire Louis Pradel Hospices Civils de Lyon Heart Failure Department Clinical Investigation Center Inserm 1407 CarMeN Inserm 1060, University Claude Bernard Lyon, Bron, France; 3 CHITS, Department of Cardiology, Hôpital Sainte-Musse, Toulon, France; 4 CHU Nantes, CNRS, INSERM, l’institut Du Thorax, Université de Nantes, Nantes, France; 5 Covidom Regional Telemedicine Platform, Assistance Publique-Hôpitaux de Paris, Paris, France; 6 Cardiology Department, University Hospital of Bicêtre, Assistance Publique-Hôpitaux de Paris, Kremlin Bicêtre, France; 7 Réseau Cardiogen, Department of Cardiology, Centre Français de Référence de l’Amylose Cardiaque (CRAC), CHU d’Henri-Mondor, Créteil, France; 8 Department of Cardiology, CHU de Lille, Université de Lille, Lille, France; 9 CIBERCV, Servicio de Cardiología, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain; 10 Robertson Centre for Biostatistics, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK; 11 Cardiology Division, Massachusetts General Hospital, Baim Institute for Clinical Research, Harvard Medical School, Boston, MA, USA; and 12 PhyMedExp, Université de Montpellier, INSERM, CNRS, Cardiology Department, CHU de Montpellier, France Received 5 October 2021; revised 4 April 2022; accepted 10 April 2022 ; online publish-ahead-of-print 27 April 2022 Management of worsening heart failure (WHF) has traditionally been hospital-based, but with the rising burden of heart failure (HF), the pressure on healthcare systems exerted by this disease necessitates a different strategy than long (and costly) hospital stays. A strategy for outpatient intravenous (IV) diuretic treatment of WHF has been developed in certain American centres in the past 10 years, whereas European centres have been mostly favouring ‘classic’ in-hospital management of WHF. Embracing novel, outpatient approaches for treating WHF could substantially reduce the burden on healthcare systems while improving patient’s satisfaction and quality of life. The present article is intended to provide essential knowledge and practical guidelines aimed at helping clinicians implement these new ambulatory approaches using day hospital and/or at-home hospitalization. The topics addressed by our group of HF experts include the pathophysiological background of diuretic therapy, the most suitable profile of WHF that may be managed in an ambulatory setting, the pharmacological protocols that can be used, as well as a detailed description of healthcare structures that can be proposed to deliver these ambulatory care interventions. The practical aspects of day hospital and hospital-at-home IV diuretic administration are specifically emphasized. The algorithm provided along with the practical IV diuretic protocols should assist HF clinicians in implementing this new approach in their local clinical setting. .......................................................................................................... Keywords Heart failure • Diuretics • Cardiac congestion • Cardiovascular diseases • Ambulatory management Introduction HF consumes approximately 9 billion euros/year of the European ................. healthcare budget. Heart failure (HF) is widely recognized as a major global public Congestion, related to pressure and/or volume overload, is health burden. HF affects 2%–3% of the adult population in West- fundamental to the pathophysiology, presentation and prognosis of ern countries1–4 and is the most common cardiovascular cause HF,5,6 irrespectively of its typology (i.e. HF with reduced [HFrEF] of hospital admission over the age of 60 years. It is estimated that vs. preserved ejection fraction [HFpEF]). Specifically, increased fluid *Corresponding author. INSERM CHU de Nancy, Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, 4 Rue du Morvan, 54500 Vandoeuvre lès Nancy, France. Tel: +33 3 83157496, Fax: +33 3 83157324, Email: nicolas_girerd@yahoo.com © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Practical outpatient management of worsening chronic HF 751 filtration due to elevated pulmonary capillary pressure leads to an increased renal natriuresis and diuresis. In an ambulatory setting, ........................................................................................................................................................................ increase in extravascular lung water resulting in pulmonary con- it is therefore important to have a sound knowledge on how to gestion and severe breathlessness in patients with HF.7,8 Conse- use and combine the different diuretic classes together,16 keeping quently, systemic congestion may also occur, often causing intesti- in mind that only a few small trials have provided, so far, evidence nal oedema and reduced absorption of guideline-directed medi- for their best use.17 cal therapies (GDMT) for HF, including loop diuretics. It usually As recently presented in a position paper of the Heart Failure presents – clinically – with various degree of lower limb oedema Association (HFA),16 the goal of diuretic therapy is to (i) obtain and substantial weight gain. Worsening symptomatic congestion is efficient decongestion, and (ii) maintain sufficient renal and organ one of the main causes leading to urgent HF hospitalization and perfusion pressures. subsequent poor patient outcomes.5,9 The cornerstone of worsen- An important facet when using diuretics in WHF patients is ing HF (WHF) treatment is intravenous (IV) loop diuretic, usually to understand their pharmacokinetics. In routine practice, many administered during hospital stays of 5–15 days (usually less in the patients with WHF have HF GDMT down-titrated or discontinued US) according to the severity of the congestive episode and the due to a mistaken interpretation of apparent worsening renal func- regional differences in healthcare structure. Importantly, patients tion (WRF)18 without an attempt to increase – substantially – or hospitalized for WHF have a high-risk of readmission, reaching up combine diuretics to achieve complete decongestion. It is hence to 50% at 6 months.10,11 Iterative hospital admissions have a major important to (i) define the optimal diuretic loading dose, (ii) impact on quality of life.12 In addition, hospitalizations by them- rapidly assess the patient’s diuretic response, and (iii) upgrade selves can be associated with iatrogenic and nosocomial complica- doses in instances of insufficient response with possible use of tions including malnutrition, infections, dependency, etc., especially sequential nephron blockade.16,19 Patients with WHF usually in elderly patients. If they could choose, many patients with chronic present with a combination of volume overload accompa- illnesses, including HF, would prefer to be treated at home, partic- nied by interstitial and bowel oedema, kidney dysfunction and ularly during, and presumably after, the COVID-19 pandemic.13 altered organ perfusion, which impairs both bioavailability of, Given the projected substantial rise in HF burden in Western and response to, diuretic therapy. Furthermore, activation of populations over the next decades, the ensuing pressure on health- the renin–angiotensin–aldosterone system (RAAS) renders the care systems exerted by HF will undoubtedly increase. In Europe, patient further resistant to oral diuretics; rising blood urea nitro- the median length of hospital stay is approximately 8 days in units gen – an indirect measure of RAAS activation – also may occur, with 24/7 trained nurses and physicians, which largely explains the masquerading as WRF. high cost of WHF management. An ambulatory management strat- The principal pharmacological properties (including site of egy for WHF has been developed in American centres in the past action) of the various diuretic classes are presented in Table 1 and 10 years (even if used heterogeneously across centres/regions),14 Figure 1. In this review, we will not address the use of acetazolamide whereas European centres (along with a number of American cen- and amiloride, being less documented, not routinely available in tres) have been mostly favouring ‘classic’ in-hospital management clinical practice in many countries and recently overviewed in detail of WHF. Embracing new approaches for managing WHF could somewhere else.16 substantially reduce the ‘burden’ of the diagnosis on European The most potent diuretic class includes loop diuretics, with healthcare systems while improving quality of life. We believe the effect of WHF on their dose–response curve presented in that there is a common interest for both patients and healthcare Figure 2.20 In the context of WHF and the consequent reduced providers to favour these ambulatory approaches to WHF. The bioavailability of oral loop diuretics, guidelines recommend the present review article is intended to provide essential knowledge use of IV loop diuretics5 to rapidly and more efficiently achieve and practical guidelines aimed at helping clinicians implement these a natriuretic ceiling.20 Different loop diuretics exist and they new ambulatory approaches using day hospital and/or at-home have different pharmacokinetics and bioavailability17 ; a large hospitalization. (∼6000 participants to be enrolled) ongoing trial is comparing Herewith, our panel of HF experts will review the pathophysio- oral torasemide to furosemide as treatment for congestion at logical background of diuretic therapy, describe the most suitable the time of discharge from an episode of HF (TRANSFORM-HF, profile of WHF which may be managed in an ambulatory setting as NCT0329681321 ) following the favourable effect of torasemide well as the pharmacological protocols that can be used, and detail on HF hospitalizations suggested in observational studies and the the healthcare setting that can be proposed to deliver these ambu- meta-analysis of small trials.22 latory care interventions. Thiazide-like diuretics can be used in severe HF patients who responded poorly to loop diuretics in a sequential nephron blockade strategy. These diuretic agents potentialize the natri- Part I: Pathophysiological uretic effect of loop diuretics (Figure 1) and in the case of oral and IV metolazone remain effective with reduced filtration rate background relevant to diuretics (<30 ml/min/1.73 m2 ).23 This effect can significantly increase diure- Patients with WHF typically have clinically significant congestion sis and should be closely monitored with serum potassium and with volume overload due to chronic retention of sodium and sodium measurements. water in the intravascular and extravascular compartments.15 In Mineralocorticoid receptor antagonists (MRAs) are seldom used this context, diuretics are used to relieve congestion through in the acute setting, although their introduction at this phase © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 752 N. Girerd et al. Table 1 Principal pharmacological properties of drugs with diuretic effects Natriuretic effect Time to peak Half-life Bioavailability Side effects when used in efficacy monotherapy (FENa%) ............................................................................................................................................................... Loop diuretics 25%–30% PO: 0.5–1 h IV: 3h Highly variable for oral Important RAAS activation 5–10 min furosemide 90% for Diuretic resistance induced bumetanide/ by compensatory DCT torsemide hypertrophy Hypokalaemia Hypomagnesaemia Hyperuricaemia Gout Thiazide-like 10% Loop diuretics PO: 1–6 h IV: only HCTZ: 6–15 h HCTZ: 65%–75% RAAS activation diuretics potentializing ++++ chlorothiazide Metolazone: 6–20 h Metolazone: 60%–65% Hypokalaemia with onset of Chlortalidone: Chlortalidone: NA Hyponatraemia 30 min 45–60 h Hyperuricaemia Gout Hypercalcaemia Hypomagnesaemia MRAs 2% PO: 48–72 h IV: Eplerenone: 3–6 h Spironolactone: 90% Hyperkalaemia potassium Canrenone: 17 h Eplerenone: 70% Average increase in serum canreonate: 2.5 h potassium: 0.4 mmol/L SGLT2i 3% Loop diuretics PO: 1.5–2 h 12 h 80%–90% Keto-acidosis (in patients potentializing ++ treated with insulin) Acetazolamide Heavily depends on PO: 2 h 6h >90% Hypokalaemia subsequent tubular Metabolic acidosis segments Hyponatraemia Amiloride 2% PO: 6 h 6–9 h 50% Hyperkalaemia Hyponatraemia DCT, distal convoluted tubule; FENa, fractional excretion of sodium; HCTZ, hydrochlorothiazide; IV, intravenous; MRA, mineralocorticoid receptor antagonist; NA, not available; PO, per os; RAAS, renin–angiotensin–aldosterone system; SGLT2i, sodium–glucose cotransporter 2 inhibitor. Adapted from Mullens et al.16 should nonetheless be considered. Together with their direct Diuretic resistance .................................................................................. inhibition of aldosterone and their potassium-sparing effect, they As noted, diuretic resistance (defined as the need for progres- can partially offset significant side-effects of loop and thiazide sive dosage up-titration in order to achieve a net fluid balance) diuretics.24 In addition, MRAs initiated in acute settings have is common in those with WHF, and corresponds to an impaired been shown to have natriuretic effects.25 Since the action of the sensitivity to diuretics resulting in reduced natriuresis. Diuretic MRA spironolactone occurs 48–72 h after oral intake (Table 1), resistance translates into a rightward shift of the dose–response eplerenone or canrenoate potassium could be favoured in the curve of sodium excretion rate with a lowering of the sodium setting of WHF.26 In the ATHENA-HF trial, spironolactone use ceiling excretion rate (Figure 2). Furthermore, WRF-associated at 100 mg/day was deemed safe and did not result in hyper- diuretic resistance is an indicator of advanced HF (as poor perfu- kalaemia or WRF (but did not improve outcome either possi- sion can favour WRF) and the need for more advanced therapies.31 bly because of the short follow-up and slow pharmacokinetics of Loop and thiazide diuretics may provide immediate symptom relief, spironolactone).27 albeit without necessarily decreasing patient mortality. Conversely, Finally, assessment of diuretic response is critical in routine consistent data have established that large doses of diuretics32,33 practice. Clinical signs of decongestion, diuresis, weight loss and and/or the need for intensification of diuretic treatments34 are renal function have limited sensitivity for guiding diuretic ther- associated with increased mortality in HF, reflecting the severity apy.28 Urinary sodium monitoring is a simple indicator of diuretic of congestion and advanced cardiac dysfunction as drivers of poor response that is associated with prognosis and has the potential outcomes.35 of becoming a useful tool for routine practice guidance of diuretic therapy.16,29 Serial measurement of natriuretic peptide concen- trations are commonly utilized in US institutions for monitoring trajectory of decongestion. Given the stability of N-terminal The impact of guideline-directed medical pro-B-type natriuretic peptide (NT-proBNP), even home-based therapies on congestion phlebotomy with centralized measurement may be performed. Both persistent congestion and excessive decongestion can lead The use of ultrasound, including serial assessment of lung B-lines, to down-titration of GDMT, mostly through renal function- and inferior vena cava or jugular vein diameter, or intra-renal venous blood pressure-related effects.36,37 Several studies have focused flow have also shown potential to be useful in this setting and is on the interaction between use of diuretics and these life-saving currently under evaluation.30 HFrEF medications. In a post-hoc analysis of the EPHESUS trial, © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Practical outpatient management of worsening chronic HF 753 Figure 1 Nephron sites and target ion channels with approximate natriuresis/diuresis effect of the various diuretic classes. Cl, chloride; ENaC, epithelial sodium channel; GFR, glomerular filtration rate; K, potassium; IV, intravenous; Na, sodium; RAAS, renin–angiotensin–aldosterone system; SE, side effect; SGLT2, sodium–glucose cotransporter 2. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 754 N. Girerd et al. Figure 2 Shift in dose–response relation to furosemide in patients with chronic heart failure (CHF). Renal function (as measured by estimated glomerular filtration rate) has an important impact on the dose–response curve to furosemide: Higher dosing is needed for lower estimated glomerular filtration rate. This is the underlying reason of the right shift observed for patients with CHF and cardiorenal syndrome and/or chronic kidney disease (CKD) (orange curve). IV, intravenous. Adapted from Brater20 patients taking eplerenone had their loop diuretic dose signifi- a significant decongestion effect45 and with likely benefit on those ......................................................................................... cantly reduced during follow-up while eplerenone benefit was with congestive complications.46 not dependent on diuretic dose.38 In a post-hoc analysis of the In the last 2 years, sodium–glucose cotransporter 2 (SGLT2) PARADIGM-HF trial, patients randomized to sacubitril/valsartan inhibitors have been shown to improve HF-related outcomes.47 had a lower subsequent use of diuretics, with fewer loop diuretic These medications induce significant natriuresis and glucosuria, dose increases and more frequent dose reductions compared with particularly when combined with loop diuretics (Figure 1), result- those taking enalapril.39 The treatment effect of sacubitril/valsartan ing in reduction in blood and plasma volume. Importantly, SGLT2 to reduce hospitalizations appeared within 30 days,40 and among inhibitors have a proximal effect, leading to a shift of tubular fluid those patients hospitalized during PARADIGM-HF, readmissions from the proximal to the distal segments of the nephron. This were lower among those treated with sacubitril/valsartan.41 Natri- shift can increase natriuresis depending on the sodium-retaining uresis is also potentialized by sacubitril through the natriuretic capacity of these distal segments (i.e. volume status, neurohu- peptide pathway.42 These results prompted the recommendation moral activation, use of diuretics). This natriuretic effect is not in all subsequent trials evaluating sacubitril/valsartan (including associated with any significant electrolyte wasting, renal dysfunc- PIONEER-HF) to consider a dose reduction in loop diuretics. tion or neurohormonal activation.48,49 Importantly, the efficacy, Moreover, in those patients with acute HF randomized to receive tolerability and safety profile of SGLT2 inhibitors is unaffected by sacubitril/valsartan in the PIONEER-HF trial, rehospitalization for concomitant treatment (or dosage) with a conventional diuretic.50 HF was substantially reduced (hazard ratio [HR] 0.61; p = 0.02).43 Most patients in the DAPA-HF trial did not undergo a change This impact of sacubitril/valsartan on congestive complications may have to do with a modest effect of sacubitril to promote natriuresis in diuretic dose during follow-up, and the mean daily dose of through boosting of natriuretic peptide concentrations.42 Support- diuretics did not differ between the dapagliflozin and placebo ing the indirect results from PARADIGM-HF, Desai and colleagues groups.51 In line with these results, in a moderately-sized trial reported early, significant reduction in pulmonary artery pressures study, Boorsma et al.15 reported that empagliflozin at a daily dose among those treated with sacubitril/valsartan (n = 96) com- of 10 mg increased plasma osmolarity without affecting fractional pared to a matched control group of 406 patients (−2.9 mmHg; sodium, chloride excretion, or urinary osmolality. However, p < 0.001); the reduction of mean pulmonary artery pressure was two studies conversely reported favourable decongestion effects greatest among those with a baseline pressure ≥30 mmHg.44 No with higher doses of empagliflozin.48,52 Despite natriuresis being predicate data exist to suggest sacubitril/valsartan has a diuretic unchanged following empagliflozin initiation in the aforemen- effect on ambulatory outpatients with WHF; however, these tioned studies, diuresis did increase in the study by Mordi et al.52 recent analyses are in keeping with a meta-analysis of older trials whereas fractional sodium excretion increased in the Griffin et al. focusing on RAAS inhibitors showing that these latter drugs have study.48 Lastly, in keeping with the impact of neprilysin inhibition © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Practical outpatient management of worsening chronic HF 755 on pulmonary artery pressures, Nassif and colleagues similarly Part II: Identification of patients ....................................................................... reported an average 12-week treatment effect of −1.7 mmHg (p = 0.02) on mean pulmonary artery pressures among patients eligible for intravenous diuretic treated with empagliflozin versus placebo.53 Trials testing use of therapy SGLT2 inhibitors in patients with diuretic resistance are ongoing (DAPA-RESIST, NCT04860011). In addition, SGLT2 inhibitors The identification of patients with WHF who are more likely were reported recently to be favourably associated with better to benefit from outpatient treatment with IV diuretics remains overall clinical outcome in the setting of WHF in the EMPULSE insufficiently documented to date. We propose an approach to the trial.54 This positive result in acute HF, in which congestion is a key use of IV diuretics in an ambulatory setting (Figure 3) along with issue, parallels the results reported in the SOLOIST-WHF trial, factors to be considered to select eligible patients (Table 2).58–63 where the rate of the primary event in patients randomized to sotagliflozin was 30% lower than in the placebo group (HR 0.67; 95% confidence interval 0.52–0.85; p < 0.001).55 The efficacy and Clinical situations unlikely to fit safety of dapagliflozin in acute HF will further be evaluated in the an ambulatory intravenous diuretic ongoing DICTATE-AHF trial.56 Of note, SGLT2 inhibitors appear programme effective in patients with HFpEF: in the EMPEROR-Preserved trial, an impressive 27% reduction in the total number of hospitalizations We suggest that patients with severe de novo HF (i.e. patients with for HF was reported in the empagliflozin group.57 markedly reduced left ventricular ejection fraction [LVEF] and New Importantly, all of these observations are derived from pro- York Heart Association [NYHA] class ≥III) should be managed in tocolized clinical and biological monitoring allowing to titrate an in-hospital setting. Indeed, these patients usually require further loop diuretic doses to patient status and no predicate data exist diagnostic and prognostic workup typically performed in hospital.60 focusing on use of SGLT2 inhibitors specifically in patients with Secondly, patients presenting with signs of shock/low cardiac WHF, however their safety/efficacy among those with congestion output, low oxygen saturation levels (i.e. peripheral oxygen sat- appears promising. uration <92%) and/or symptoms at rest (NYHA class IV) should Figure 3 Framework for ambulatory intravenous (IV) diuretics use. AF, atrial fibrillation; ER, emergency room; GP, general practitioner; HF, heart failure; NYHA, New York Heart Association; PE, pulmonary embolism; WHF, worsening heart failure. © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 756 N. Girerd et al. It is likely that these ambulatory IV diuretic programmes could ........................................................................................................................................................................ Table 2 Factors to be considered to select patients be especially efficient in patients implanted with a CardioMEMS to be treated with intravenous diuretics in an device,65 as it allows an early detection of increased pulmonary ambulatory setting pressure. In favour Against Importantly, a number of patients do not feel sufficiently ill to ......................................................................... require in-hospital admission. Yet their management based solely Clinical scenarios Progressive worsening First episode of HF60 on oral diuretics is troublesome. There is thus a ‘grey zone’ of HF58,59 Critical trigger61 (rapid HR: 50–120 bpm61 arrhythmias, acute patients too ill to be managed with oral diuretics but not sufficiently SBP >100 mmHg61 coronary syndrome) ill to necessitate an emergency room visit. In these ‘grey-zone’ SaO2 >92%61 NYHA class IV61 scenarios, local availability of an ambulatory IV diuretics service Alert from remote HF Anasarca58,59 monitoring61 can be widely accepted and effective to improve congestion before HF profiles Cardiac amyloidosis62 Very high dose of oral it reaches the threshold for in-hospital admission. diuretics (500 mg or In all instances, the clinical response to IV diuretic sessions more furosemide/day) Comorbidities Frailty63 Severely impaired eGFR should be carefully assessed, through a dedicated local disease man- Palliative care63 (i.e. <25 ml/min/ agement protocol, involving one or several of the following health- (especially for hospital at 1.73 m2 )61 care professionals: HF nurses, local nurses, general practitioners home) Severe dysnatraemia, dyskalaemia or and treating cardiologists. anaemia61 Social criteria Patient preference63 Difficult/unsanitary living Adequate living conditions63 (for at support63 home hospital) Part III: Diuretics in ambulatory eGFR, estimated glomerular filtration rate; HF, heart failure; HR, heart rate; NYHA, New York settings – how to proceed? Heart Association; SaO2 , arterial oxygen saturation; SBP, systolic blood pressure. The protocol published by Buckley et al.58 (adapted in Figure 4) has been used in more than 250 patients14,59 and sets a good foundation be also managed in hospital. The clinical suspect, or identification, for implementation strategies. This protocol has also been used, of specific and potentially fatal triggers of clinical deterioration, for with some local adjustments/amendments,66 by our group on a instance a rapid conduction of supraventricular arrhythmias, pul- regular basis in the last few years. monary embolism or acute coronary syndromes14,58 should also Briefly, diuretic sessions consist in a 3-h IV diuretic infusion, prompt in-hospital management. performed the same day or next-day treatment. The pharma- Explosive/rapid worsening does not leave an adequate window cological approach is contingent on the maintenance diuretic for intervening in an outpatient setting. Nevertheless, this clinical dose: patients with the highest oral diuretic maintenance dose scenario does not exclude early discharge with subsequent ambu- would receive the highest IV diuretics (and possibly co-diuretics latory IV diuretic management. such as thiazides). Generally, hydrochlorothiazide doses between 12.5 to 50 mg/session are used; metolazone 2.5 to 5 mg may be vey effective in those with estimated glomerular filtration rate Clinical situations most likely to fit <30 ml/min/1.73 m2 . In such patients, IV metolazone or chloroth- iazide may also be given; however the advantage of oral thiazide an ambulatory intravenous diuretic administration makes it preferred. If sequential nephron blockade programme is utilized with an oral thiazide, the oral medication is administered Episodes of progressive WHF are very common, and represent 30 min prior to the IV loop diuretic. Thiazide has occasionally been the most frequent causes of a HF hospitalization (65% of cases replaced by a high-dose IV MRA by some members of our group in the EuroHeart Failure Survey II64 ). Refractory symptoms and in similar settings given the natriuretic and diuretic properties of signs of congestion despite high doses of oral loop diuretics are MRAs,67 including IV MRAs.26 The main advantage of MRA in this major concerns for patients with severe HF. Indeed, these patients setting is to offset the primum movens of diuretic resistance, i.e. represent the main target population of ambulatory treatment the key involvement of RAAS – in sharp contrast with thiazide with IV diuretics, as they spend a substantial amount of time in that further increases RAAS activation. Acetazolamide is another hospital (‘frequent flyers’), which impairs their quality of life fur- option to consider in multi-site nephron blockade.68 In the setting ther and is associated with substantial costs. This particular phe- of ‘hospital at home’ (HaH), only IV boluses of loop diuretics are notype corresponds to the population originally targeted by the typically used, singly or divided to twice a day. Brigham and Women’s Hospital group in their initial experience Importantly, the subcutaneous form of furosemide has been of ambulatory IV diuretics: most (80%) had mild–moderate symp- developed in recent years.69 These subcutaneous injections are toms, with a median maintenance diuretic dose of 240 mg oral particularly useful in at-home hospital settings as they are logisti- furosemide.58 cally demanding and do not require the hurdle/inconvenience of Similarly, this approach has been proposed in patients with repeated venous puncture. cardiac amyloidosis,62 a population who also experiences multiple Careful consideration should be paid to dyskalaemia following episodes of WHF and poor quality of life. the IV diuretic session. Briefly, with this protocol, only patients with © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Practical outpatient management of worsening chronic HF 757 Figure 4 Ambulatory intravenous (IV) diuretics protocol according to maintenance loop diuretic dose. These doses are general guidelines that need to be adapted to renal function. Patients with estimated glomerular filtration rate <30 ml/min/1.73 m2 usually need higher (usually doubled) diuretic dose. ARNi, angiotensin receptor–neprilysin inhibitor; BP, blood pressure; HR, heart rate; MRA, mineralocorticoid receptor antagonist; RAASi, renin–angiotensin–aldosterone inhibitor; SGLT2i, sodium–glucose cotransporter 2 inhibitor. prior IV diuretic potassium >4 mEq/L (regardless of renal function) patients receiving IV diuretic sessions are likely to have increased .............. or patients with K+ >3.7 if creatinine is 2.0 mg/dl (175 μmol/L) or doses of oral diuretics in the following weeks, which could further above will not receive potassium supplements during the IV diuretic decrease serum potassium levels. sessions (Figure 4). In our experience, these patients with low Of importance, guideline-recommended drugs should not serum potassium should receive MRAs whenever possible. Indeed, be withheld during this IV diuretic period, unless symptomatic © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 758 N. Girerd et al. hypotension occurs. Indeed, as already emphasized above, RAAS is obviously not possible in a consultation setting and requires ........................................................................................................................................................................ is a key driver of sodium/water retention. dedicated space and resources. A nurse would be devoted to the There are sparse data assessing the optimal number of diuretic surveillance of the patient’s vitals every hour, as well as verify sessions. Very early follow-up overviewed by a physician should diuresis and natriuresis, and perform blood tests if needed. In a be undertaken to assess the clinical efficacy of the IV sessions day-hospital setting, early low diuresis can be offset using thiazide (ideally within 48–72 h). Additional sessions should be performed or MRA during the second half of the infusion session, thanks to if substantial congestion persists. Clinical deterioration or a the close monitoring of the nurse. decrease in diuretic efficacy should prompt in-hospital admis- At the end of the session, the patient’s status is reassessed to sion in most instances. Our general threshold to discontinue determine whether the IV infusion was sufficiently effective for iterative ambulatory IV diuretics is reported in Figure 3, and the patient to be discharged and plans are made for subsequent includes a mixture of clinical response, objective evaluation, infusions. Typically, two–three infusions during the first week of and laboratory testing (which can include natriuretic peptide treatment for WHF are needed to achieve decongestion and quantification). improve clinical status. In most severe cases, a continuous infusion of IV diuretics for 6 h may be required, which will be perceived much less negatively by the patient than regular hospitalizations Part IV: How to organize requiring overnight stay. In the next days, an ambulatory short-term healthcare in order to successfully telemonitoring is useful to verify the favourable impact of the diuretic assault. Repeated natriuretic peptide measurements can perform ambulatory intravenous also be useful to monitor decongestion. diuretics? A day-hospital setting has additional benefits. For instance, it can favour a multidisciplinary approach and, during the day-hospital Hospital at home management, patients can be cared for by therapeutic education ‘Hospital at home’ or ‘home hospitalization’ may be used following nurses, dieticians, and other healthcare professionals for additional in-hospital care. This approach can favour the reduction in length counselling and re-evaluation aiming at preventing further episodes of in-hospital stay, as patients will be closely followed in this home of decongestion. setting following a short initial in-hospital admission. During HaH, In order to be efficiently used, as in the case of home hospital- in addition to the use of IV diuretics, high-risk behaviours limiting ization, this facility should be easily accessible to eligible patients. HF care efficacy can be identified (since home is the setting of Typically, day-hospital sessions should be performed within 24 to care).70,71 48 h of the identification of moderate WHF during a consultation Not all patients are eligible for this HaH approach. Patient at an HF clinic, within disease management programmes or home selection begins with a geriatric and social assessment, involving monitoring. To maximize efficacy, the coordinative link between patient, caregiver(s), attending physician and, if applicable, nurses the day hospital and these other facilities should be optimal, and social workers. The second step is to determine who will possibly included in the same parent organization/network. This be responsible for the patient’s treatment – either the patient’s integration is crucial since a close follow-up is needed following general practitioner or a cardiologist. the IV infusions to determine whether additional sessions are In our experience, the success of HaH following in-hospital required. As for ‘classical’ WHF requiring ward hospitalizations, management of WHF relies on daily nursing assessment (weight, congestion episodes tend to recur. These relapses need to be blood pressure, heart rate, oximetry and symptoms), home biology quickly managed in additional day-hospital sessions, within an and electrocardiogram, remote access to online patient chart, organized healthcare network. secured remote prescription, close nursing duty, medical on-call service and a process for urgent consultation or rehospitalization. The efficacy of HaH for HF has been recently systematically Part V: Management following reviewed by Qaddoura et al.72 The conclusion of this meta-analysis ambulatory intravenous diuretic was that only a limited number (three trials totalizing 203 patients and three cohorts totalizing 329 patients) of modest-quality stud- treatment ies were available, in which HaH appears to increase time to Background HFrEF treatment readmission, reduce index costs, and improve quality of life.72 Notwithstanding the latter, larger trials such as the SAFE-HOME optimization (NCT03156686) and FIL-EAS (NCT04878263) trials are needed Given the significant decongestion effect of RAAS inhibitors45 and to accumulate definitive evidence. rapid improvement in outcome after initiation of contemporary GDMT, every attempt should be made to optimize the non-loop diuretic HF GDMT after the resolution of congestive episodes Day hospital following ambulatory IV diuretic therapy. The up-titration of drugs Much of the published clinical experience regarding ambulatory IV (initiation/switch to sacubitril/valsartan, as well as initiation of MRA diuretics is currently derived from a day-hospital setting.58 This and SGLT2 inhibitors) could be perceived as difficult to achieve in outpatient venue enables delivering 3-h IV diuretic infusion, which this context given that WRF is often observed during or following © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. Practical outpatient management of worsening chronic HF 759 WHF. A practical approach to HF treatment management in the (3) Formal endorsement by healthcare insurance providers: ........................................................................................................................................................................ setting of WRF18 and low blood pressure37 has moreover been these pathways need to be funded (and possibly promoted) published. Importantly, in the month following the IV diuretic by the health insurance sector. session, we recommend a weekly assessment by an HF physician (4) Formalized approach to medical responsibility. In an ambula- or nurse practitioner in order to adjust the diuretic dose and tory setting, determining who is the physician in charge of the optimize/up-titrate the GDMT. patient’s management may be less straightforward than in an inpatient setting. (5) Formalized process 24/7 for ‘rescue’ management by emer- HFpEF and HFmrEF treatment gency departments. optimization (6) Health data transfer/exchange between the different health- Importantly, patients with HFpEF and HFrEF are similarly affected care providers. by WHF and diuretic strategies in ambulatory clinics appear to have similar benefit for those with HFpEF as it did for HFrEF.58 The main limitation of the implementation of the approach Medical optimization is advisable for patients with HFpEF (LVEF proposed herein could be its actual integration within the patient’s ≥50%) or HF with mildly reduced ejection fraction (HFmrEF; immediate healthcare environment. Ambulatory care may be LVEF 41%–49%) following decongestion. Initiation/up-titration of impossible or impractical if the local health network is not suf- MRAs73 in this setting may be associated with better outcome and ficiently reliable or adapted to perform such management. The should be considered in patients with HFpEF. In the PARAGON-HF minimum requirements for the implementation of ambulatory study, use of sacubitril/valsartan for patients with LVEF ≥45% IV management likely include: (i) clinicians available for clinical was associated with reduction of HF hospitalizations in patients reassessment, treatment adjustments, and triage toward hos- with LVEF <55% and women.74 In the EMPEROR-Preserved trial, pitalization or urgent visits in HF clinics, (ii) nurses available at empagliflozin reduced HF hospitalizations by 27% (p < 0.001) in home for blood sampling/tests, clinical assessment (weight, vital patients with LVEF >40%.57 signs), (iii) social support (meals at home, for instance), and (iv) a direct link of these professionals with a dedicated HF team. All How to down-titrate diuretics after should be efficiently connected through a healthcare coordination framework, ideally available 24/7, but more realistically, operating a temporary increase in ambulatory during regular hours. Importantly, some of these issues could patients? be alleviated by telemonitoring, e.g. for changes in weight or Despite the importance of loop diuretics in HF management and symptoms, and empowering patients and their careers.76 related adverse events, little effort has focused on ‘optimizing’ diuretics. A number of tools could help optimize diuretic treat- Conclusion ment, including natriuretic peptide monitoring,75 pulmonary arte- rial pressure remote monitoring,65 or serial ultrasound imaging of The rising pressure on healthcare systems will preclude continu- the inferior vena cava, but in routine practice only clinical assess- ing treating all episodes of WHF with lengthy hospital admissions. ment is used in the vast majority of cases. Importantly, the first Therefore, there is a mutual interest for both patients and health- step should be to establish whether the previous dose should be care providers to favour ambulatory therapeutic approaches that considered as the correct posology or whether a higher dose is deliver IV diuretics to improve congestion and well-being, and save required. As a general rule, if the previous dose did not prevent costs and resources. Future trials will clarify safety and effective- WHF, a higher dose should be maintained for at least 3–4 weeks. ness of these models of care and identify patients more likely to Reinforcing GDMT will eventually help the down-titration of loop gain benefits. It is likely that ambulatory delivery of IV diuretics will diuretics. soon no longer be an option, but rather a new norm. Part VI: Barriers to the Acknowledgements implementation of these The authors acknowledge technical support from Novartis for illustrations. Novartis provided financial support for logistic man- healthcare organizations agement and was not involved in the preparation/drafting of the There are several existing barriers to overcome in the application manuscript. of these new patient management pathways: Funding (1) Limited clinical trial evidence (despite a larger use in observa- Profs Girerd and Rossignol are supported by a public grant tional studies14 ) to document the efficacy or non-inferiority overseen by the French National Research Agency (ANR) of these alternative therapeutic approaches. as part of the second “Investissements d’Avenir” programme (2) Further validation of the protocols for the use of diuretics (ANR-15-RHU-0004). and associated drugs: dose validation, IV access, periodicity, Conflict of interest: N.G. received board fees from Novartis. clinical and laboratory monitoring. N.M. declares consultant, honoraria, research, and travel grants © 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. 760 N. Girerd et al. from Novartis, Bayer and MSD. J.M.T. received personal fees from 10. Girerd N, Seronde MF, Coiro S, Chouihed T, Bilbault P, Braun F, et al.; INI-CRCT, ........................................................................................................................................................................ Great Network, and the EF-HF Group. Integrative assessment of congestion in Novartis and AstraZeneca; non-financial support from Novartis, heart failure throughout the patient journey. JACC Heart Fail. 2018;6:273–85. AstraZeneca and Amgen and was principal investigator in tri- 11. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Crespo Leiro M, Drozdz als involving Novartis, Amgen, Servier, Bayer and Merck Sharp J, et al. 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