IJCA-18404; No of Pages 6 International Journal of Cardiology xxx (2014) xxx–xxx
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Review
Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure Massimo Piepoli a, Simone Binno a,b, Giovanni Quinto Villani a, Aderville Cabassi b,⁎ a b
Heart Failure Unit, Cardiology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy Cardiorenal Research Unit, Department of Clinical and Experimental Medicine, Parma University School of Medicine, Parma, Italy
a r t i c l e
i n f o
Article history: Received 22 October 2013 Received in revised form 21 July 2014 Accepted 26 July 2014 Available online xxxx Keywords: Acute decompensated heart failure Oral therapy Diuretics beta-blockers ACE-inhibitors Angiotensin receptor blockers
a b s t r a c t Acute decompensated heart failure (ADHF) is the most common cause of cardiovascular hospitalization. The presentation is characterized by different clinical profiles due to various underlying causes, volume balance and tissue perfusion status. Currently, a variety of pharmacological therapies, including diuretics, betablockers, ACE-inhibitors, angiotensin receptor blockers and digoxin, are usually prescribed in order to treat chronic heart failure (HF) syndromes caused by left ventricular systolic dysfunction. Despite the large number of HF patients with frequent hospitalizations for decompensation, only a few studies have evaluated the management of oral chronic therapies in the clinical setting of ADHF. This article summarizes the information derived from the few published trials on this subject and a therapeutic approach is suggested with respect to the continuation, dose modification or suspension of oral medications. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction Acute decompensated heart failure (ADHF) is a syndrome characterized by rapid or gradual onset of signs and symptoms of heart failure, leading to unplanned hospital admissions or office and emergency room visits [1]. Hospital admission for heart failure represents 1–2% of all hospitalizations in the Western world [2,3]. Patients affected with HF have a high rate of mortality during hospital stay and after hospital discharge, with a high rate of readmission that varies from 15 to 22% within the first 30 days to 35–45% at 90 days [4–7]. ADHF can be differentiated as a new onset of HF (30–40%) or a worsening of chronic HF [8,9]. There is common concern regarding the
Abbreviations: ACE, angiotensin converting enzyme; ADHF, acute decompensated heart failure; ARB, angiotensin receptor blocker; B-CONVINCED, beta-blocker continuation vs. interruption in patients with congestive heart failure hospitalized for a decompensation episode; COMET, Carvedilol or Metoprolol European Trial; COPD, chronic obstructive pulmonary disease; EF, ejection fraction; ESCAPE, evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness; HF, heart failure; MRA, mineralocorticoid receptor antagonist; NSAIDs, non-steroidal anti-inflammatory drugs; OPTIMIZEHF, organized program to initiate lifesaving treatment in hospitalized patients with heart failure; PDE III, phosphodiesterase III; RAAS, renin–angiotensin–aldosterone system; TOPCAT, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. ⁎ Corresponding author at: Cardiorenal Research Unit, Physiopathology Unit, CardioNephro-Pulmonary Department, Department of Clinical and Experimental Medicine, University Hospital School of Medicine, Via Gramsci 14, 43126 Parma, Italy. Tel.: + 39 0521033191; fax: +39 0521033185. E-mail address: [email protected] (A. Cabassi).
management of oral therapies in the setting of ADHF due to worsening of chronic HF. This is linked to the fear of worsening the clinical syndrome because chronic treatment could contrast compensatory mechanisms acting to sustain pump function and organ perfusion. There are also doubts on discontinuation or dose reduction of oral therapies that could be unnecessary during the decompensated phase. Another concern is related to the possibility of poor absorption of oral drugs during the acute phases [10]. Recent evidence indicates that continuation with little change in oral therapy may be not only feasible but may also favorably affect the outcome of ADHF patients [11]. This paper aims to consider the physiological background and the rationale of continuing or changing oral therapies in the setting of patients with ADHF related to the worsening of chronic HF and to suggest practical tools for their management.
2. ADHF classification, clinical features and treatment goals Different classifications have been proposed for ADHF. A common one is based on six categories following clinical and etiological profiles [5,12–14]. This classification, reported in the 2008 edition, but no longer used in the up to date European Society of Cardiology 2012 guidelines, was based on hemodynamic severity and pathophysiological classes and applied to both acute de novo HF patients and to patients with worsening chronic HF [4,5]. The distinction between acute de novo and worsening of chronic HF is important because different mechanisms of adaptations are predominant in the clinical presentation of these two groups of patients. Our paper mainly focuses on the
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Please cite this article as: Piepoli M, et al, Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.085
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management of oral therapies in patients with acute decompensation of chronic HF. Another classification, based on the evidence of congestion and adequate perfusion in ADHF patients, is endowed with prognostic significance (Fig. 1) [6,15–17]. This classification better frames the true hemodynamic profile of these subjects and appears more practical to assist in the selection and the titration of treatments. This classification is best suited for patients with acute decompensation of chronic HF [6, 17]. ADHF patients are then classified as “warm and dry” if their clinical presentation is characterized by euvolemia and adequate perfusion, as “warm and wet” if they are congested and adequately perfused, as “cold and dry” if they are hypoperfused and euvolemic, and finally “cold and wet” if they are hypoperfused and congested. The term “wet” of the clinical profiles of patients with ADHF is related to the presence of fluid overload. Pulmonary congestion is not necessarily the same as fluid overload, in fact a hemodynamic derangement with a rise in pulmonary venous pressure without a systemic excess of fluid represents the mechanism of decompensation of HF in acute pulmonary edema: this indicates the need for reduction in filling pressure with a vasodilator more than net fluid removal with a diuretic [18]. There are several precipitating factors responsible for decompensation including poor therapeutic compliance, inadequate pharmacological therapy, administration of inappropriate drugs (such as NSAIDs, COXIBs, antiarrhythmic agents, non-dihydropyridine calcium-antagonists), fluid overload (by excessive salt or fluid ingestion or iatrogenic if the patient is hospitalized), uncontrolled hypertension, arrhythmias (slow or fast), pulmonary infection or COPD exacerbation, sepsis, myocardial infarction, valvular disease progression, cardiac tamponade, aortic dissection, myocarditis, and endocrine or hematologic disorders (anemia, thyroid disorders) [5,19]. The treatment goals in ADHF patients are first, the relief of symptoms and the identification and correction of precipitating factors, and second, the improvement of post-discharge mortality and the prevention of hospital readmission. The four clinical profiles described above may also define different prognostic categories. The clinical profile “warm and dry”, representing almost one third of patients, describes a group of patients with a good overall prognosis, generally related to ADHF due to uncontrolled hypertension. In the “warm and dry” clinical profile group, the objective is the treatment of uncontrolled hypertension and the titration of oral betablockers and renin–angiotensin–aldosterone system (RAAS) active therapies. The worst prognosis group is represented by the “cold and
wet” clinical profile, which holds a two-fold higher death risk when compared with the “warm and dry” profile [17]. About half of the ADHF patients are admitted with a “warm and wet” clinical profile, and they carry a better prognosis when compared with the “cold and wet” group [6]. They need relief from congestion and therefore the initial treatment should be focused on diuretic therapy. The “cold and wet” clinical profile of ADHF (around 20% of ADHF patients) presentation requires a more intensive therapy to achieve adequate perfusion and to solve the congestion. Vasodilating inotropes may be helpful as initial treatment. The clinical “cold and dry” profile represents the few patients with ADHF who have significantly reduced cardiac reserve without significant congestion [6,17]. They need an intervention aimed at tissue perfusion and the emphasis should be on inotropic support and careful fluid repletion with hemodynamic monitoring. 3. Oral pharmacological therapy management The medical treatment for chronic HF patients is based on preload and afterload reduction (using ACE-inhibitors, ARBs and diuretics), and inhibition of deleterious neurohormonal activation (RAAS and sympathetic nervous system) using ACE-inhibitors, ARBs, mineralocorticoid receptor antagonists (MRAs) and beta-blockers. The mentioned therapies have been demonstrated to prolong survival and reduced hospital readmission in HF patients with reduced left ventricle ejection fraction (EF) [4,20–28]. None of these treatments has convincingly been shown to reduce mortality and hospital admission in HF patients with preserved EF. Afterload reduction obtained by inhibiting both the RAAS and sympathetic nervous systems produces vasodilation, thereby increasing cardiac output and decreasing myocardial oxygen demand, which represents another fundamental goal [4,20]. Diuretics are the main treatment to relieve symptoms induced by positive fluid balance; they are effective in preload reduction by increasing urinary sodium excretion and decreasing fluid retention, which improves cardiac function and exercise tolerance [4]. In addition, preload reduction results in decreased pulmonary capillary hydrostatic pressure and reduction of fluid transudation into the pulmonary interstitium and alveoli. All these effects of diuretics on preload and afterload reduction provide symptomatic relief. An issue of major concern in all patients admitted to the hospital for ADHF is related to the necessity to maintain, modify or stop ongoing oral medical treatments.
Evidence for Congeson?
Evidence for Low Perfusion?
No
Yes
No
Warm and Dry profile
Warm and Wet profile
Yes
Cold and Dry profile
Cold and Wet profile
Fig. 1. Classification scheme for assigning clinical profile in patients with ADHF. Patients may be defined “warm” when there is adequate tissue perfusion, or “cold” when the perfusion is compromised, evaluating the extremities temperature-status. The patients may also be defined “wet”, indicating pulmonary congestion or “dry” in the absence of pulmonary congestion, evaluating the presence of lungs edema or rales.
3.1. Diuretics Diuretics remain the cornerstone of standard therapy for ADHF, and the intravenous administration of a loop diuretic (i.e., furosemide, bumetanide, torsemide) is initially preferred because of the potentially lower absorption of the oral form in the presence of bowel edema in HF [10]. Given the potential reduced intestinal absorption of diuretics during the hypervolemic status of ADHF (“warm and wet” and “cold and wet” clinical patient profiles) and altered pharmacokinetics and pharmacodynamics of diuretics, intravenous administration of loop diuretics is needed. In fact, patients admitted for ADHF and already on therapy with oral diuretics should be switched to an i.v. loop diuretic [4,20]. Loop diuretic use should always be associated with a correct monitoring of fluid balance including intake and excretion. After i.v. administration of loop diuretics, the transition to oral therapy is possible when the patient reaches a near-euvolemic state. The oral loop diuretic dose is usually equal to the i.v. dose except for furosemide, whose mean oral bioavailability is 60%, and so the dose should be doubled to obtain a similar diuretic effect. In most cases, 40 mg/day of furosemide is equivalent to 20 mg of torsemide and 1 mg of bumetanide. Body weight, diuresis, signs and symptoms of heart failure, fluid balance, electrolyte
Please cite this article as: Piepoli M, et al, Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.085
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levels, and renal function have to be monitored carefully on a daily basis [29]. One of the most important elements, necessary for prolonged efficacy of a loop diuretic and to prevent the development of resistance, is represented by water and salt restriction in patients with congestion and edema. As reported in the last recommendations for treating ADHF, fluid and sodium restriction are among the nonpharmacologic interventions, and this appears an intuitively reasonable statement [20]. However, recent data from a small randomized controlled trial comparing an aggressive fluid (800 mL/day) and salt restriction (800 mg/day) diet to a regular diet showed no significant differences in weight loss, urine output, clinical congestion improvement, amount of intravenous diuretics, and time to discharge from a hospital [30]. Two other studies confirm that, in patients admitted with ADHF, aggressive fluid and salt restriction did not provide clinical benefit during hospitalization [31,32]. All these results appear counterintuitive and suggest that the negative or neutral effects are related by the authors to an excessive neurohormonal activation linked to the aggressive sodium restriction. Even if it is recognized that excessive sodium and fluid intake may precipitate ADHF in advanced HF patients [33], the strength of the actual data on sodium restriction recommendation is modest and definitive and clear conclusions cannot be drawn. However, for patients with ADHF, aggressive salt restriction is not recommended at the moment, but a moderate sodium restriction (b 3 g/day) should be considered by clinicians to improve congestion symptoms and prevent the development of diuretic resistance. In ADHF patients who continue to exhibit signs and symptoms of congestion, despite an adequate loop diuretic therapy, a state of resistance may develop. In a recently published trial (Diuretic Optimization Strategies Evaluation — DOSE) a strategy with higher doses of i.v. loop diuretics (doubling the usual oral dose of loop diuretic), offered advantages in terms of greater diuresis, weight loss, and relief of dyspnea (more effective decongestion and lowering natriuretic peptide levels), without any identified long-term disadvantages compared to a strategy of maintaining the usual oral dose administered i.v. Even the higher rate of worsening of renal function at 72 h observed in high dose diuretic strategy, was transient and not associated with any signal of worsening long-term outcomes [34]. If diuretic resistance develops, a second approach is the concomitant administration of a second diuretic agent, a thiazide-type, which blocks the distal tubule sodium resorption by inhibiting the Na/Cl co-transporter and provides significant augmentation of diuresis. The most common combinations with loop diuretics are with metolazone (2.5 to 10 mg), or hydrochlorothiazide (25–200 mg), or bendroflumethiazide (5–10 mg), or chlorothiazide (500 mg), which can be orally administered [35]. Although it is a common opinion that a thiazide-type diuretic should be given at least half an hour before the loop diuretic, the majority of studies report benefits when the diuretics are administered at the same time [35]. As described by Jentzer et al., this leads to two important effects: 1) antagonism of the renal adaptation to chronic loop diuretic therapy, and 2) improvement or reversal of loop diuretic resistance due to rebound sodium resorption [35]. This enhanced diuresis could potentially lead to faster symptom relief, more effective overall weight reduction, and shorter length of hospital stay with fewer subsequent readmissions, especially in patients demonstrating a substantial degree of diuretic resistance and/or with significant renal dysfunction. However, these questions have not been carefully evaluated in prospective controlled clinical trials, and the risk/benefit ratio of thiazide diuretic addition remains uncertain. Therefore the combination of diuretics should be attentively weighted. The potential benefits imparted by the addition of a thiazide-type diuretic must be balanced against the potential risks of electrolyte and metabolic abnormalities. Hypokalemia is a frequent consequence of the sequential nephron blockade that results from combining a thiazide
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diuretic such as metolazone with a loop diuretic [36]. Hypomagnesemia, hypochloremic metabolic alkalosis, and hyponatremia are also potential concerns. Careful monitoring of electrolytes is a critical part of preventing the morbidity and mortality associated with arrhythmic events [37]. 3.2. Angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) The benefit of ACE-inhibitors in HF patients was established at least 20 years ago in two major randomized trials and meta-analysis [21,22, 38]. They showed an increase in survival, a reduction of hospital readmissions, an improvement in NYHA class and quality of life in patients with all grades of symptomatic HF with reduced EF. In patients with symptomatic HF, the ARBs valsartan and candesartan have been shown, in two major randomized trials and its substudies [39–42] to reduce HF hospital admissions, improve NYHA class and maintain quality of life. Therefore, in patients not already receiving an ACE-inhibitor or ARB, these drugs should be started as soon as possible, blood pressure and renal function permitting. In patients admitted to the hospital because of ADHF and already in therapy with RAAS antagonists, a temporary withdrawal of ACEinhibitors or ARBs may be necessary in cases of severe or symptomatic hypotension, defined by systolic blood pressure b90 mm Hg, or the development of oliguric/anuric status, or a rise in serum creatinine levels more than 2.5 mg/dL (221 μmol/L), or an increase more than or equal to 0.3 mg/dL (greater than or equal to 26.5 μmol/L), or an increase to more than or equal to 150% to 200% (1.5- to 2-fold) from creatinine baseline value [43]. Attention should be paid to prevent the development of hyperkalemia. Drug interactions to look out for K + supplements/ K + sparing diuretics e.g., amiloride and triamterene (beware of combination preparations with furosemide), aldosterone antagonists (spironolactone, eplerenone), angiotensin receptor blockers, NSAIDS* and “low salt” substitutes with a high K + content, due to possible pathological raise in plasma K + levels [44,45]. Another point to be considered is the presence of a renal dysfunction which may worsen if hypotension or an excessive volume-depletion occurs, making a temporary withdrawal of ACE-inhibitors or ARB drugs necessary [46]. In patients admitted with azotemia or acute renal failure, temporary reduction or discontinuation of ACE-inhibitors or angiotensin-receptor blockers may be necessary. Consequently, routine use of ACE inhibitors, or ARBs in the setting of severe renal dysfunction (serum creatinine levels greater than 2.5 mg/dL (221 μmol/L)) is not recommended [47]. In this situation, volume status and clinical perfusion in heart failure patients must be carefully assessed daily, and this includes measuring body weight, urine output, blood pressure, serum electrolytes and renal function. Once stabilized, before discharge, the ACE inhibitor (or ARB) dosage should be up-titrated as far as possible and a plan made to complete dose up-titration after discharge. Usually, patients with the “warm and dry” clinical profile of admission are the best candidates for an optimization of ACE-inhibitor/ARB therapy, with a control of plasma creatinine and electrolytes at every step of up-titration, to identify the possible deterioration in kidney function. In patients admitted for ADHF and a “warm and wet” profile, oral therapies can be maintained, avoiding an up-titration and checking electrolytes and creatinine levels until the resolution of congestion and the restoration of euvolemic status. During the intense diuretic therapy, renal function can transiently deteriorate, and further worse with a concomitant increase in ACE-i/ARB dose. In ADHF patients, where clinical manifestations of tissue hypoperfusion are predominant and with profiles of “cold and dry” and especially
Please cite this article as: Piepoli M, et al, Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.085
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“cold and wet”, the temporary discontinuation of treatments acting on RAAS inhibition is mandatory. The primary need is to restore an adequate blood pressure and peripheral tissue perfusion and to avoid evolution into an anuric/oliguric status and acute kidney failure (Table 1). When the goal of a proper peripheral tissue perfusion is reached, with an adequate normal blood pressure, urine output and a stable renal function parameters, ACE-i/ARB drugs can be reintroduced, planning an up-titration after hospital discharge.
3.3. Beta-blocker Beta-blocker therapy is a well-established treatment of chronic HF, leading to an amelioration of symptoms, to reverse left ventricular remodeling, to the improvement in systolic function, to fewer hospitalization and lower mortality rates [24–26,48]. In contrast to the big amount of data in chronic HF, data available on beta-blocker therapy use in symptomatic ADHF are scarce. The dilemma whether to reduce the dose or to stop beta-blocker therapy, which has a negative inotropic effect during ADHF, is of increasing importance in current clinical practice. In the last decade, beta-blockers became more widespread in hospitalized HF patients because of ADHF [49]. Less strong and in particular less supported by evidence from randomized clinical trials are the recommendations about management of patients with acutely decompensated heart failure treated with beta-blocker. ESC guidelines state that in patients admitted to hospital due to worsening heart failure, a reduction in the dose of beta-blockers may be necessary, and that in severe situations, temporary discontinuation can be considered [4]; these recommendations are based on observational data and questions remain regarding the safety and efficacy of this approach. Although theoretical justifications may be possible for continuation or discontinuation of beta-blocker therapy on admission in ADHF patients, the data from studies that specifically addressed this issue is scarce and the available informations are often extracted from subset of patients in bigger trials. In fact, data from a retrospective sub-study of the ESCAPE trial, where pulmonary artery catheter use was evaluated in patients hospitalized for ADHF, indicate that the continuation of beta-blocker therapy during hospitalization was associated with a lower mortality and rehospitalization rate at six months after discharge. Patients, in whom beta-blockers were withdrawn, were more tachycardiac and tachypneic on admission, had lower ejection fraction, and were more likely to develop hypotension during hospitalization [50], but the limit of a retrospective evaluation is evident. Also in a sub-study of the COMET, two-year mortality rates were lower in the group maintaining beta-blocker dosage than in the groups of beta-blocker where treatment was withdrawn or reduced [51].
In a sub-study of the hospital-based registry (OPTIMIZE-HF), the Authors evaluated in a usual care ward the relationship between continuation or withdrawal of beta-blockers and clinical outcomes in patients hospitalized for ADHF. The continuation was associated with a significantly lower adjusted post-discharge death and death or rehospitalization compared with those not treated with beta-blockers. In contrast, withdrawal of beta-blocker therapy was associated with a worse adjusted risk for mortality [52]. B-CONVINCED is the first prospective randomized trial where Jondeau et al. specifically examined the strategy of continuation versus discontinuation of chronic beta-blocker therapy during acute decompensation of systolic HF [53]. The study included patients hospitalized for acute HF with pulmonary edema and left ventricular ejection fraction less than 40%, and excluded those with a clinical indication for dobutamine. After 3 and 8 days no differences were observed in dyspnea and general well-being, indicating non-inferiority for continuation of beta-blockers between groups. Plasma B-type natriuretic peptide levels, lengths of hospital stays, rehospitalization rates and death rates after 3 months were also similar between the two groups [53]. However, concerns were reported about this trial regarding the potential bias of selection related to the under-representation of other populations with ADHF (pulmonary edema represented less than one quarter of the total amount of patients admitted for ADHF), the small size and the lower dosage of beta-blockers used in the study [11]. From a practical point of view, the clinical profile of ADHF patients may guide the strategy of withdrawing or maintaining beta-blocker therapy and eventually titrating the dose. Patients with “warm and dry” profiles may benefit and safely tolerate an up-titration of beta-blockers whereas the clinical presentation of the “warm and wet” profile might represent a population where chronic beta-blocker therapy could be maintained but the up-titration deferred until restoration of euvolemia. Conversely, patients with the “cold and dry” clinical profile might need a reduction or withdrawal of beta-blocker therapy depending on the tissue perfusion levels. In the case of “cold and wet” clinical profile, where the primary needs are represented by inotropic and diuretic treatment, betablocker therapy should be withdrawn until perfusion and congestion are normalized. However, if the deterioration of clinical status is characterized by hypoperfusion and requires the use of intravenous positive inotropic drugs, it may be prudent to halt or significantly reduce treatment with beta-blockers until the status of the patient stabilizes. In such patients, positive inotropic agents whose effects are mediated independently from the beta receptor (e.g., a phosphodiesterase III (PDE III) inhibitor such as milrinone, or levosimendan) may be preferred [54–57].
Table 1 Management of oral therapy in AHF. The recommendations in this table represent expert opinion based upon relevant clinical trials and clinical experience. When indicated, the dose should be decreased by one-half, and the patient should be reassessed. If the dose is reduced, it should be uptitrated to the previous well-tolerated dose as soon as safely possible. Diuretics Warm and dry Euvolemic, normal perfusion Warm and wet Congestion, normal perfusion Cold and dry Euvolemic or hypovolemic, low perfusion Cold and wet Congestion, low perfusion
ACE-i/ARB
Beta-blocker
Maintain or reduce, if possible Maintain/increase checking Maintain/increase renal function Increase dosage or associate a second diuretic drug
Digoxin
Maintain/increase
Usually non needed. Maintain
Maintain, defer up-titration Maintain, defer up-titration
Reduce with caution/maintain Reduce/withdraw
Evaluate every single case
MRA
Withdraw
Maintain, defer up-titration Maintain Verify the plasma concentration Reduce/withdraw Maintain Reduce/withdraw Verify the plasma Evaluate needing of concentration inotropic support Withdraw Maintain Withdraw Verify the plasma Evaluate needing of inotropic concentration support
ACE-i: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; and MRA: Mineralocorticoid receptor antagonist.
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Once stabilized, beta-blocker should be reintroduced to reduce the subsequent risk of clinical deterioration. Although it has been shown that continuation of β-blockers for most patients is well tolerated and results in better outcomes, particular attention should be used when their dosage is maintained or uptitrated during acute exacerbation of heart failure. In fact, in the presence of hemodynamic instability and with the potential necessity of dobutamine inotrope therapy, it is reasonable to reduce or withdraw the beta-blocker therapy (Table 1). In conclusion, unless the patient is in shock or in a high-grade heart block, there is no clear need to discontinue the beta-blocker, while it may be prudent to reduce the dose or defer an eventual up-titration. 3.4. Mineralocorticoid (aldosterone) receptor antagonist (MRA) In patients with reduced ejection fraction not already receiving an MRA, this treatment should be started as soon as possible, renal function and potassium permitting. Similarly to ACE-inhibitors, in the setting of severe renal dysfunction (serum creatinine levels greater than 2.5 mg/dL (221 μmol/L) or an increase of more than 50% from baseline), a MRA is not routinely recommended. In the recent TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) the addition of spironolactone on top of the best therapy in HF patients with a preserved EF was not able to reduce mortality from cardiovascular causes or hospital admission rates. In addition, having excluded patients with severe renal insufficiency (eGFR less than 30 mL/min), the arm treated with spironolactone presented a higher incidence of hyperkalemia and an increase in serum creatinine levels, emphasizing the need for close monitoring of renal function and electrolytes during these treatments [58]. As the dose of MRA used to treat HF has a minimal effect on blood pressure, even relatively hypotensive patients may be started on this therapy during admission. The dose should be up-titrated as far as possible before discharge, and a plan made to complete dose uptitration after discharge. A safe and effective introduction of MRAs in ADHF depends on appropriate patient selection regarding renal function and potassium levels. In fact renal impairment is present in the majority of patients admitted with ADHF, and worsening renal function occurs in at least 30% of patients during hospitalization and in 20% of patients shortly after discharge [59]. In patients treated with MRA before admission, particular caution should be given if a patient with ADHF is on concomitant ACE-inhibitor or ARB therapy, because of the risk of hyperkalemia, and in those with a reduced renal function these drugs should be reduced or stopped (Table 1). 3.5. Digoxin In patients with reduced ejection fraction, digoxin may be used to control the ventricular rate in atrial fibrillation, especially if it has not been possible to up-titrate the dose of beta-blockers. Digoxin may also provide symptom relief and reduce the risk of HF hospitalization in patients with severe systolic HF, but has no benefit on mortality reduction [60]. When a patient is treated with digoxin prior to admission for ADHF associated with acute renal failure, it is reasonable to check its plasma level, especially in patients with oliguria or anuria, to avoid toxic effects related to its plasma accumulation [61]. 3.6. Tolvaptan Tolvaptan, an oral nonpeptide selective vasopressin V2-receptor antagonist, used in addition to standard therapy including diuretics, has been shown to improve dyspnea. In a subgroup of patients presenting low systolic blood pressure and renal impairment, who often do not
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respond adequately and may not tolerate traditional diuretic therapy, tolvaptan improved symptoms, reduced body weight and increased serum sodium as early as inpatient day 1 without adversely affecting blood pressure or renal function [62]. 4. Conclusion The management of oral therapies during the hospitalization of patients for ADHF represents a challenge in current clinical practice. Congestion reduction and improvement in peripheral perfusion are the main goals. Changes in oral therapies may be indicated, taking into careful consideration the risk of adverse effects or of aggravating unstable condition as well as the effect that inopportune discontinuation of effective drugs may have on outcome. The oral therapies usually prescribed, such as ACE-inhibitors, ARB, beta-blocker, diuretics, MRAs and digoxin have changed the prognosis and the quality of life of HF patients. However, despite the large number of patients with HF and the frequent hospitalizations for decompensation of HF, only few studies have evaluated the management of oral chronic therapies in the ADHF. More studies are needed for each single pharmacological class and their combination in this frequent clinical setting. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Nieminen MS, Harjola VP. Definition and epidemiology of acute heart failure syndromes. Am J Cardiol 2005;96(6A):5G–10G. [2] Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63(12):1123–33. [3] Alla F, Zannad F, Filippatos G. Epidemiology of acute heart failure syndromes. Heart Fail Rev 2007;12(2):91–5. [4] McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787–847. [5] Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388–442. [6] Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am Coll Cardiol 2003;41(10):1797–804 [21]. [7] Grady KL, Dracup K, Kennedy G, et al. Team management of patients with heart failure: a statement for healthcare professionals from the Cardiovascular Nursing Council of the American Heart Association. Circulation 2000;102(19):2443–56. [8] Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27(22):2725–36. [9] Maggioni AP, Dahlström U, Filippatos G, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013;15(7):808–17. [10] Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC. Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med 1985;102(3): 314–8. [11] Swedberg K. Beta-blockers in worsening heart failure: good or bad? Eur Heart J 2009;30:2177–9. [12] Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53: 557–73. [13] Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958–68. [14] Joseph SM, Cedars AM, Ewald GA, Geltman EM, Mann DL. Acute decompensated heart failure. Tex Heart Inst J 2009;36:510–20. [15] Stevenson LW, Massie BM, Francis GS. Optimizing therapy for complex or refractory heart failure: a management algorithm. Am Heart J 1998;135(6 Pt 2 Su):S293–309. [16] Shah MR, Hasselblad V, Stinnett SS, et al. Hemodynamic profiles of advanced heart failure: association with clinical characteristics and long-term outcomes. J Card Fail 2001;7(2):105–13.
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[40] Pfeffer MA, Swedberg K, Granger C, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362(9386):759–66. [41] McMurray JJ, Ostergren J, Swedberg K, 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(9386):767–71. [42] Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative Trial. Lancet 2003;362(9386):772–6. [43] Endre ZH. Acute kidney injury: definitions and new paradigms. Adv Chronic Kidney Dis 2008;15:213–21. [44] Nyirenda MJ, Tang JI, Padfield PL, Seckl JR. Hyperkalaemia. BMJ 2009;339:b4114. [45] Doorenbos CJ, Vermeij CG. Danger of salt substitutes that contain potassium in patients with renal failure. BMJ 2003;326(7379):35–6. [46] Heywood JT. The cardiorenal syndrome: lessons from the ADHERE database and treatment options. Heart Fail Rev 2004;9(3):195–201. [47] Arnold JM, Howlett JG, Dorian P, et al. Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update 2007: prevention, management during intercurrent illness or acute decompensation, and use of biomarkers. Can J Cardiol 2007;23(1):21–45. [48] Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–25. [49] Adams Jr KF, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149(2):209–16. [50] Butler J, Young JB, Abraham WT, et al. Beta-blocker use and outcomes among hospitalized heart failure patients. J Am Coll Cardiol 2006;47(12):2462–9. [51] Metra M, Torp-Pedersen C, Cleland JG, et al. Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET. Eur J Heart Fail 2007;9(9):901–9. [52] Fonarow GC, Abraham WT, Albert NM, et al. Influence of beta-blocker continuation or withdrawal on outcomes in patients hospitalized with heart failure: findings from the OPTIMIZE-HF program. J Am Coll Cardiol 2008;52:190–9. [53] Jondeau G, Neuder Y, Eicher JC, et al. B-CONVINCED: beta-blocker continuation vs. interruption in patients with congestive heart failure hospitalized for a decompensation episode. Eur Heart J 2009;30:2186–92. [54] Lowes BD, Tsvetkova T, Eichhorn EJ, Gilbert EM, Bristow MR. Milrinone versus dobutamine in heart failure subjects treated chronically with carvedilol. Int J Cardiol 2001;81:141–9. [55] Jennings DL, Thompson ML. Use of combination therapy with a beta-blocker and milrinone in patients with advanced heart failure. Ann Pharmacother 2009;43:1872–6. [56] Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002;360(9328):196–202. [57] Mebazaa A, Nieminen MS, Filippatos GS, et al. Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail 2009;11:304–11. [58] Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370(15):1383–92. [59] Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011;32:2626–33. [60] [No authors listed]The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525–33 [20]. [61] Doherty JE, Dalrymple GV, Murphy ML, Kane JJ, Bissett JK, de Soyza N. Pharmacokinetics of digoxin. Fed Proc 1977;36:2242–6. [62] Vaduganathan M, Gheorghiade M, Pang PS, et al. Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment. J Cardiovasc Med (Hagerstown) 2012;13:415–22.
Please cite this article as: Piepoli M, et al, Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.085
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Review
Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure Massimo Piepoli a, Simone Binno a,b, Giovanni Quinto Villani a, Aderville Cabassi b,⁎ a b
Heart Failure Unit, Cardiology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy Cardiorenal Research Unit, Department of Clinical and Experimental Medicine, Parma University School of Medicine, Parma, Italy
a r t i c l e
i n f o
Article history: Received 22 October 2013 Received in revised form 21 July 2014 Accepted 26 July 2014 Available online xxxx Keywords: Acute decompensated heart failure Oral therapy Diuretics beta-blockers ACE-inhibitors Angiotensin receptor blockers
a b s t r a c t Acute decompensated heart failure (ADHF) is the most common cause of cardiovascular hospitalization. The presentation is characterized by different clinical profiles due to various underlying causes, volume balance and tissue perfusion status. Currently, a variety of pharmacological therapies, including diuretics, betablockers, ACE-inhibitors, angiotensin receptor blockers and digoxin, are usually prescribed in order to treat chronic heart failure (HF) syndromes caused by left ventricular systolic dysfunction. Despite the large number of HF patients with frequent hospitalizations for decompensation, only a few studies have evaluated the management of oral chronic therapies in the clinical setting of ADHF. This article summarizes the information derived from the few published trials on this subject and a therapeutic approach is suggested with respect to the continuation, dose modification or suspension of oral medications. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction Acute decompensated heart failure (ADHF) is a syndrome characterized by rapid or gradual onset of signs and symptoms of heart failure, leading to unplanned hospital admissions or office and emergency room visits [1]. Hospital admission for heart failure represents 1–2% of all hospitalizations in the Western world [2,3]. Patients affected with HF have a high rate of mortality during hospital stay and after hospital discharge, with a high rate of readmission that varies from 15 to 22% within the first 30 days to 35–45% at 90 days [4–7]. ADHF can be differentiated as a new onset of HF (30–40%) or a worsening of chronic HF [8,9]. There is common concern regarding the
Abbreviations: ACE, angiotensin converting enzyme; ADHF, acute decompensated heart failure; ARB, angiotensin receptor blocker; B-CONVINCED, beta-blocker continuation vs. interruption in patients with congestive heart failure hospitalized for a decompensation episode; COMET, Carvedilol or Metoprolol European Trial; COPD, chronic obstructive pulmonary disease; EF, ejection fraction; ESCAPE, evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness; HF, heart failure; MRA, mineralocorticoid receptor antagonist; NSAIDs, non-steroidal anti-inflammatory drugs; OPTIMIZEHF, organized program to initiate lifesaving treatment in hospitalized patients with heart failure; PDE III, phosphodiesterase III; RAAS, renin–angiotensin–aldosterone system; TOPCAT, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial. ⁎ Corresponding author at: Cardiorenal Research Unit, Physiopathology Unit, CardioNephro-Pulmonary Department, Department of Clinical and Experimental Medicine, University Hospital School of Medicine, Via Gramsci 14, 43126 Parma, Italy. Tel.: + 39 0521033191; fax: +39 0521033185. E-mail address: [email protected] (A. Cabassi).
management of oral therapies in the setting of ADHF due to worsening of chronic HF. This is linked to the fear of worsening the clinical syndrome because chronic treatment could contrast compensatory mechanisms acting to sustain pump function and organ perfusion. There are also doubts on discontinuation or dose reduction of oral therapies that could be unnecessary during the decompensated phase. Another concern is related to the possibility of poor absorption of oral drugs during the acute phases [10]. Recent evidence indicates that continuation with little change in oral therapy may be not only feasible but may also favorably affect the outcome of ADHF patients [11]. This paper aims to consider the physiological background and the rationale of continuing or changing oral therapies in the setting of patients with ADHF related to the worsening of chronic HF and to suggest practical tools for their management.
2. ADHF classification, clinical features and treatment goals Different classifications have been proposed for ADHF. A common one is based on six categories following clinical and etiological profiles [5,12–14]. This classification, reported in the 2008 edition, but no longer used in the up to date European Society of Cardiology 2012 guidelines, was based on hemodynamic severity and pathophysiological classes and applied to both acute de novo HF patients and to patients with worsening chronic HF [4,5]. The distinction between acute de novo and worsening of chronic HF is important because different mechanisms of adaptations are predominant in the clinical presentation of these two groups of patients. Our paper mainly focuses on the
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management of oral therapies in patients with acute decompensation of chronic HF. Another classification, based on the evidence of congestion and adequate perfusion in ADHF patients, is endowed with prognostic significance (Fig. 1) [6,15–17]. This classification better frames the true hemodynamic profile of these subjects and appears more practical to assist in the selection and the titration of treatments. This classification is best suited for patients with acute decompensation of chronic HF [6, 17]. ADHF patients are then classified as “warm and dry” if their clinical presentation is characterized by euvolemia and adequate perfusion, as “warm and wet” if they are congested and adequately perfused, as “cold and dry” if they are hypoperfused and euvolemic, and finally “cold and wet” if they are hypoperfused and congested. The term “wet” of the clinical profiles of patients with ADHF is related to the presence of fluid overload. Pulmonary congestion is not necessarily the same as fluid overload, in fact a hemodynamic derangement with a rise in pulmonary venous pressure without a systemic excess of fluid represents the mechanism of decompensation of HF in acute pulmonary edema: this indicates the need for reduction in filling pressure with a vasodilator more than net fluid removal with a diuretic [18]. There are several precipitating factors responsible for decompensation including poor therapeutic compliance, inadequate pharmacological therapy, administration of inappropriate drugs (such as NSAIDs, COXIBs, antiarrhythmic agents, non-dihydropyridine calcium-antagonists), fluid overload (by excessive salt or fluid ingestion or iatrogenic if the patient is hospitalized), uncontrolled hypertension, arrhythmias (slow or fast), pulmonary infection or COPD exacerbation, sepsis, myocardial infarction, valvular disease progression, cardiac tamponade, aortic dissection, myocarditis, and endocrine or hematologic disorders (anemia, thyroid disorders) [5,19]. The treatment goals in ADHF patients are first, the relief of symptoms and the identification and correction of precipitating factors, and second, the improvement of post-discharge mortality and the prevention of hospital readmission. The four clinical profiles described above may also define different prognostic categories. The clinical profile “warm and dry”, representing almost one third of patients, describes a group of patients with a good overall prognosis, generally related to ADHF due to uncontrolled hypertension. In the “warm and dry” clinical profile group, the objective is the treatment of uncontrolled hypertension and the titration of oral betablockers and renin–angiotensin–aldosterone system (RAAS) active therapies. The worst prognosis group is represented by the “cold and
wet” clinical profile, which holds a two-fold higher death risk when compared with the “warm and dry” profile [17]. About half of the ADHF patients are admitted with a “warm and wet” clinical profile, and they carry a better prognosis when compared with the “cold and wet” group [6]. They need relief from congestion and therefore the initial treatment should be focused on diuretic therapy. The “cold and wet” clinical profile of ADHF (around 20% of ADHF patients) presentation requires a more intensive therapy to achieve adequate perfusion and to solve the congestion. Vasodilating inotropes may be helpful as initial treatment. The clinical “cold and dry” profile represents the few patients with ADHF who have significantly reduced cardiac reserve without significant congestion [6,17]. They need an intervention aimed at tissue perfusion and the emphasis should be on inotropic support and careful fluid repletion with hemodynamic monitoring. 3. Oral pharmacological therapy management The medical treatment for chronic HF patients is based on preload and afterload reduction (using ACE-inhibitors, ARBs and diuretics), and inhibition of deleterious neurohormonal activation (RAAS and sympathetic nervous system) using ACE-inhibitors, ARBs, mineralocorticoid receptor antagonists (MRAs) and beta-blockers. The mentioned therapies have been demonstrated to prolong survival and reduced hospital readmission in HF patients with reduced left ventricle ejection fraction (EF) [4,20–28]. None of these treatments has convincingly been shown to reduce mortality and hospital admission in HF patients with preserved EF. Afterload reduction obtained by inhibiting both the RAAS and sympathetic nervous systems produces vasodilation, thereby increasing cardiac output and decreasing myocardial oxygen demand, which represents another fundamental goal [4,20]. Diuretics are the main treatment to relieve symptoms induced by positive fluid balance; they are effective in preload reduction by increasing urinary sodium excretion and decreasing fluid retention, which improves cardiac function and exercise tolerance [4]. In addition, preload reduction results in decreased pulmonary capillary hydrostatic pressure and reduction of fluid transudation into the pulmonary interstitium and alveoli. All these effects of diuretics on preload and afterload reduction provide symptomatic relief. An issue of major concern in all patients admitted to the hospital for ADHF is related to the necessity to maintain, modify or stop ongoing oral medical treatments.
Evidence for Congeson?
Evidence for Low Perfusion?
No
Yes
No
Warm and Dry profile
Warm and Wet profile
Yes
Cold and Dry profile
Cold and Wet profile
Fig. 1. Classification scheme for assigning clinical profile in patients with ADHF. Patients may be defined “warm” when there is adequate tissue perfusion, or “cold” when the perfusion is compromised, evaluating the extremities temperature-status. The patients may also be defined “wet”, indicating pulmonary congestion or “dry” in the absence of pulmonary congestion, evaluating the presence of lungs edema or rales.
3.1. Diuretics Diuretics remain the cornerstone of standard therapy for ADHF, and the intravenous administration of a loop diuretic (i.e., furosemide, bumetanide, torsemide) is initially preferred because of the potentially lower absorption of the oral form in the presence of bowel edema in HF [10]. Given the potential reduced intestinal absorption of diuretics during the hypervolemic status of ADHF (“warm and wet” and “cold and wet” clinical patient profiles) and altered pharmacokinetics and pharmacodynamics of diuretics, intravenous administration of loop diuretics is needed. In fact, patients admitted for ADHF and already on therapy with oral diuretics should be switched to an i.v. loop diuretic [4,20]. Loop diuretic use should always be associated with a correct monitoring of fluid balance including intake and excretion. After i.v. administration of loop diuretics, the transition to oral therapy is possible when the patient reaches a near-euvolemic state. The oral loop diuretic dose is usually equal to the i.v. dose except for furosemide, whose mean oral bioavailability is 60%, and so the dose should be doubled to obtain a similar diuretic effect. In most cases, 40 mg/day of furosemide is equivalent to 20 mg of torsemide and 1 mg of bumetanide. Body weight, diuresis, signs and symptoms of heart failure, fluid balance, electrolyte
Please cite this article as: Piepoli M, et al, Management of oral chronic pharmacotherapy in patients hospitalized for acute decompensated heart failure, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.085
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levels, and renal function have to be monitored carefully on a daily basis [29]. One of the most important elements, necessary for prolonged efficacy of a loop diuretic and to prevent the development of resistance, is represented by water and salt restriction in patients with congestion and edema. As reported in the last recommendations for treating ADHF, fluid and sodium restriction are among the nonpharmacologic interventions, and this appears an intuitively reasonable statement [20]. However, recent data from a small randomized controlled trial comparing an aggressive fluid (800 mL/day) and salt restriction (800 mg/day) diet to a regular diet showed no significant differences in weight loss, urine output, clinical congestion improvement, amount of intravenous diuretics, and time to discharge from a hospital [30]. Two other studies confirm that, in patients admitted with ADHF, aggressive fluid and salt restriction did not provide clinical benefit during hospitalization [31,32]. All these results appear counterintuitive and suggest that the negative or neutral effects are related by the authors to an excessive neurohormonal activation linked to the aggressive sodium restriction. Even if it is recognized that excessive sodium and fluid intake may precipitate ADHF in advanced HF patients [33], the strength of the actual data on sodium restriction recommendation is modest and definitive and clear conclusions cannot be drawn. However, for patients with ADHF, aggressive salt restriction is not recommended at the moment, but a moderate sodium restriction (b 3 g/day) should be considered by clinicians to improve congestion symptoms and prevent the development of diuretic resistance. In ADHF patients who continue to exhibit signs and symptoms of congestion, despite an adequate loop diuretic therapy, a state of resistance may develop. In a recently published trial (Diuretic Optimization Strategies Evaluation — DOSE) a strategy with higher doses of i.v. loop diuretics (doubling the usual oral dose of loop diuretic), offered advantages in terms of greater diuresis, weight loss, and relief of dyspnea (more effective decongestion and lowering natriuretic peptide levels), without any identified long-term disadvantages compared to a strategy of maintaining the usual oral dose administered i.v. Even the higher rate of worsening of renal function at 72 h observed in high dose diuretic strategy, was transient and not associated with any signal of worsening long-term outcomes [34]. If diuretic resistance develops, a second approach is the concomitant administration of a second diuretic agent, a thiazide-type, which blocks the distal tubule sodium resorption by inhibiting the Na/Cl co-transporter and provides significant augmentation of diuresis. The most common combinations with loop diuretics are with metolazone (2.5 to 10 mg), or hydrochlorothiazide (25–200 mg), or bendroflumethiazide (5–10 mg), or chlorothiazide (500 mg), which can be orally administered [35]. Although it is a common opinion that a thiazide-type diuretic should be given at least half an hour before the loop diuretic, the majority of studies report benefits when the diuretics are administered at the same time [35]. As described by Jentzer et al., this leads to two important effects: 1) antagonism of the renal adaptation to chronic loop diuretic therapy, and 2) improvement or reversal of loop diuretic resistance due to rebound sodium resorption [35]. This enhanced diuresis could potentially lead to faster symptom relief, more effective overall weight reduction, and shorter length of hospital stay with fewer subsequent readmissions, especially in patients demonstrating a substantial degree of diuretic resistance and/or with significant renal dysfunction. However, these questions have not been carefully evaluated in prospective controlled clinical trials, and the risk/benefit ratio of thiazide diuretic addition remains uncertain. Therefore the combination of diuretics should be attentively weighted. The potential benefits imparted by the addition of a thiazide-type diuretic must be balanced against the potential risks of electrolyte and metabolic abnormalities. Hypokalemia is a frequent consequence of the sequential nephron blockade that results from combining a thiazide
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diuretic such as metolazone with a loop diuretic [36]. Hypomagnesemia, hypochloremic metabolic alkalosis, and hyponatremia are also potential concerns. Careful monitoring of electrolytes is a critical part of preventing the morbidity and mortality associated with arrhythmic events [37]. 3.2. Angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) The benefit of ACE-inhibitors in HF patients was established at least 20 years ago in two major randomized trials and meta-analysis [21,22, 38]. They showed an increase in survival, a reduction of hospital readmissions, an improvement in NYHA class and quality of life in patients with all grades of symptomatic HF with reduced EF. In patients with symptomatic HF, the ARBs valsartan and candesartan have been shown, in two major randomized trials and its substudies [39–42] to reduce HF hospital admissions, improve NYHA class and maintain quality of life. Therefore, in patients not already receiving an ACE-inhibitor or ARB, these drugs should be started as soon as possible, blood pressure and renal function permitting. In patients admitted to the hospital because of ADHF and already in therapy with RAAS antagonists, a temporary withdrawal of ACEinhibitors or ARBs may be necessary in cases of severe or symptomatic hypotension, defined by systolic blood pressure b90 mm Hg, or the development of oliguric/anuric status, or a rise in serum creatinine levels more than 2.5 mg/dL (221 μmol/L), or an increase more than or equal to 0.3 mg/dL (greater than or equal to 26.5 μmol/L), or an increase to more than or equal to 150% to 200% (1.5- to 2-fold) from creatinine baseline value [43]. Attention should be paid to prevent the development of hyperkalemia. Drug interactions to look out for K + supplements/ K + sparing diuretics e.g., amiloride and triamterene (beware of combination preparations with furosemide), aldosterone antagonists (spironolactone, eplerenone), angiotensin receptor blockers, NSAIDS* and “low salt” substitutes with a high K + content, due to possible pathological raise in plasma K + levels [44,45]. Another point to be considered is the presence of a renal dysfunction which may worsen if hypotension or an excessive volume-depletion occurs, making a temporary withdrawal of ACE-inhibitors or ARB drugs necessary [46]. In patients admitted with azotemia or acute renal failure, temporary reduction or discontinuation of ACE-inhibitors or angiotensin-receptor blockers may be necessary. Consequently, routine use of ACE inhibitors, or ARBs in the setting of severe renal dysfunction (serum creatinine levels greater than 2.5 mg/dL (221 μmol/L)) is not recommended [47]. In this situation, volume status and clinical perfusion in heart failure patients must be carefully assessed daily, and this includes measuring body weight, urine output, blood pressure, serum electrolytes and renal function. Once stabilized, before discharge, the ACE inhibitor (or ARB) dosage should be up-titrated as far as possible and a plan made to complete dose up-titration after discharge. Usually, patients with the “warm and dry” clinical profile of admission are the best candidates for an optimization of ACE-inhibitor/ARB therapy, with a control of plasma creatinine and electrolytes at every step of up-titration, to identify the possible deterioration in kidney function. In patients admitted for ADHF and a “warm and wet” profile, oral therapies can be maintained, avoiding an up-titration and checking electrolytes and creatinine levels until the resolution of congestion and the restoration of euvolemic status. During the intense diuretic therapy, renal function can transiently deteriorate, and further worse with a concomitant increase in ACE-i/ARB dose. In ADHF patients, where clinical manifestations of tissue hypoperfusion are predominant and with profiles of “cold and dry” and especially
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“cold and wet”, the temporary discontinuation of treatments acting on RAAS inhibition is mandatory. The primary need is to restore an adequate blood pressure and peripheral tissue perfusion and to avoid evolution into an anuric/oliguric status and acute kidney failure (Table 1). When the goal of a proper peripheral tissue perfusion is reached, with an adequate normal blood pressure, urine output and a stable renal function parameters, ACE-i/ARB drugs can be reintroduced, planning an up-titration after hospital discharge.
3.3. Beta-blocker Beta-blocker therapy is a well-established treatment of chronic HF, leading to an amelioration of symptoms, to reverse left ventricular remodeling, to the improvement in systolic function, to fewer hospitalization and lower mortality rates [24–26,48]. In contrast to the big amount of data in chronic HF, data available on beta-blocker therapy use in symptomatic ADHF are scarce. The dilemma whether to reduce the dose or to stop beta-blocker therapy, which has a negative inotropic effect during ADHF, is of increasing importance in current clinical practice. In the last decade, beta-blockers became more widespread in hospitalized HF patients because of ADHF [49]. Less strong and in particular less supported by evidence from randomized clinical trials are the recommendations about management of patients with acutely decompensated heart failure treated with beta-blocker. ESC guidelines state that in patients admitted to hospital due to worsening heart failure, a reduction in the dose of beta-blockers may be necessary, and that in severe situations, temporary discontinuation can be considered [4]; these recommendations are based on observational data and questions remain regarding the safety and efficacy of this approach. Although theoretical justifications may be possible for continuation or discontinuation of beta-blocker therapy on admission in ADHF patients, the data from studies that specifically addressed this issue is scarce and the available informations are often extracted from subset of patients in bigger trials. In fact, data from a retrospective sub-study of the ESCAPE trial, where pulmonary artery catheter use was evaluated in patients hospitalized for ADHF, indicate that the continuation of beta-blocker therapy during hospitalization was associated with a lower mortality and rehospitalization rate at six months after discharge. Patients, in whom beta-blockers were withdrawn, were more tachycardiac and tachypneic on admission, had lower ejection fraction, and were more likely to develop hypotension during hospitalization [50], but the limit of a retrospective evaluation is evident. Also in a sub-study of the COMET, two-year mortality rates were lower in the group maintaining beta-blocker dosage than in the groups of beta-blocker where treatment was withdrawn or reduced [51].
In a sub-study of the hospital-based registry (OPTIMIZE-HF), the Authors evaluated in a usual care ward the relationship between continuation or withdrawal of beta-blockers and clinical outcomes in patients hospitalized for ADHF. The continuation was associated with a significantly lower adjusted post-discharge death and death or rehospitalization compared with those not treated with beta-blockers. In contrast, withdrawal of beta-blocker therapy was associated with a worse adjusted risk for mortality [52]. B-CONVINCED is the first prospective randomized trial where Jondeau et al. specifically examined the strategy of continuation versus discontinuation of chronic beta-blocker therapy during acute decompensation of systolic HF [53]. The study included patients hospitalized for acute HF with pulmonary edema and left ventricular ejection fraction less than 40%, and excluded those with a clinical indication for dobutamine. After 3 and 8 days no differences were observed in dyspnea and general well-being, indicating non-inferiority for continuation of beta-blockers between groups. Plasma B-type natriuretic peptide levels, lengths of hospital stays, rehospitalization rates and death rates after 3 months were also similar between the two groups [53]. However, concerns were reported about this trial regarding the potential bias of selection related to the under-representation of other populations with ADHF (pulmonary edema represented less than one quarter of the total amount of patients admitted for ADHF), the small size and the lower dosage of beta-blockers used in the study [11]. From a practical point of view, the clinical profile of ADHF patients may guide the strategy of withdrawing or maintaining beta-blocker therapy and eventually titrating the dose. Patients with “warm and dry” profiles may benefit and safely tolerate an up-titration of beta-blockers whereas the clinical presentation of the “warm and wet” profile might represent a population where chronic beta-blocker therapy could be maintained but the up-titration deferred until restoration of euvolemia. Conversely, patients with the “cold and dry” clinical profile might need a reduction or withdrawal of beta-blocker therapy depending on the tissue perfusion levels. In the case of “cold and wet” clinical profile, where the primary needs are represented by inotropic and diuretic treatment, betablocker therapy should be withdrawn until perfusion and congestion are normalized. However, if the deterioration of clinical status is characterized by hypoperfusion and requires the use of intravenous positive inotropic drugs, it may be prudent to halt or significantly reduce treatment with beta-blockers until the status of the patient stabilizes. In such patients, positive inotropic agents whose effects are mediated independently from the beta receptor (e.g., a phosphodiesterase III (PDE III) inhibitor such as milrinone, or levosimendan) may be preferred [54–57].
Table 1 Management of oral therapy in AHF. The recommendations in this table represent expert opinion based upon relevant clinical trials and clinical experience. When indicated, the dose should be decreased by one-half, and the patient should be reassessed. If the dose is reduced, it should be uptitrated to the previous well-tolerated dose as soon as safely possible. Diuretics Warm and dry Euvolemic, normal perfusion Warm and wet Congestion, normal perfusion Cold and dry Euvolemic or hypovolemic, low perfusion Cold and wet Congestion, low perfusion
ACE-i/ARB
Beta-blocker
Maintain or reduce, if possible Maintain/increase checking Maintain/increase renal function Increase dosage or associate a second diuretic drug
Digoxin
Maintain/increase
Usually non needed. Maintain
Maintain, defer up-titration Maintain, defer up-titration
Reduce with caution/maintain Reduce/withdraw
Evaluate every single case
MRA
Withdraw
Maintain, defer up-titration Maintain Verify the plasma concentration Reduce/withdraw Maintain Reduce/withdraw Verify the plasma Evaluate needing of concentration inotropic support Withdraw Maintain Withdraw Verify the plasma Evaluate needing of inotropic concentration support
ACE-i: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; and MRA: Mineralocorticoid receptor antagonist.
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Once stabilized, beta-blocker should be reintroduced to reduce the subsequent risk of clinical deterioration. Although it has been shown that continuation of β-blockers for most patients is well tolerated and results in better outcomes, particular attention should be used when their dosage is maintained or uptitrated during acute exacerbation of heart failure. In fact, in the presence of hemodynamic instability and with the potential necessity of dobutamine inotrope therapy, it is reasonable to reduce or withdraw the beta-blocker therapy (Table 1). In conclusion, unless the patient is in shock or in a high-grade heart block, there is no clear need to discontinue the beta-blocker, while it may be prudent to reduce the dose or defer an eventual up-titration. 3.4. Mineralocorticoid (aldosterone) receptor antagonist (MRA) In patients with reduced ejection fraction not already receiving an MRA, this treatment should be started as soon as possible, renal function and potassium permitting. Similarly to ACE-inhibitors, in the setting of severe renal dysfunction (serum creatinine levels greater than 2.5 mg/dL (221 μmol/L) or an increase of more than 50% from baseline), a MRA is not routinely recommended. In the recent TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) the addition of spironolactone on top of the best therapy in HF patients with a preserved EF was not able to reduce mortality from cardiovascular causes or hospital admission rates. In addition, having excluded patients with severe renal insufficiency (eGFR less than 30 mL/min), the arm treated with spironolactone presented a higher incidence of hyperkalemia and an increase in serum creatinine levels, emphasizing the need for close monitoring of renal function and electrolytes during these treatments [58]. As the dose of MRA used to treat HF has a minimal effect on blood pressure, even relatively hypotensive patients may be started on this therapy during admission. The dose should be up-titrated as far as possible before discharge, and a plan made to complete dose uptitration after discharge. A safe and effective introduction of MRAs in ADHF depends on appropriate patient selection regarding renal function and potassium levels. In fact renal impairment is present in the majority of patients admitted with ADHF, and worsening renal function occurs in at least 30% of patients during hospitalization and in 20% of patients shortly after discharge [59]. In patients treated with MRA before admission, particular caution should be given if a patient with ADHF is on concomitant ACE-inhibitor or ARB therapy, because of the risk of hyperkalemia, and in those with a reduced renal function these drugs should be reduced or stopped (Table 1). 3.5. Digoxin In patients with reduced ejection fraction, digoxin may be used to control the ventricular rate in atrial fibrillation, especially if it has not been possible to up-titrate the dose of beta-blockers. Digoxin may also provide symptom relief and reduce the risk of HF hospitalization in patients with severe systolic HF, but has no benefit on mortality reduction [60]. When a patient is treated with digoxin prior to admission for ADHF associated with acute renal failure, it is reasonable to check its plasma level, especially in patients with oliguria or anuria, to avoid toxic effects related to its plasma accumulation [61]. 3.6. Tolvaptan Tolvaptan, an oral nonpeptide selective vasopressin V2-receptor antagonist, used in addition to standard therapy including diuretics, has been shown to improve dyspnea. In a subgroup of patients presenting low systolic blood pressure and renal impairment, who often do not
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respond adequately and may not tolerate traditional diuretic therapy, tolvaptan improved symptoms, reduced body weight and increased serum sodium as early as inpatient day 1 without adversely affecting blood pressure or renal function [62]. 4. Conclusion The management of oral therapies during the hospitalization of patients for ADHF represents a challenge in current clinical practice. Congestion reduction and improvement in peripheral perfusion are the main goals. Changes in oral therapies may be indicated, taking into careful consideration the risk of adverse effects or of aggravating unstable condition as well as the effect that inopportune discontinuation of effective drugs may have on outcome. The oral therapies usually prescribed, such as ACE-inhibitors, ARB, beta-blocker, diuretics, MRAs and digoxin have changed the prognosis and the quality of life of HF patients. However, despite the large number of patients with HF and the frequent hospitalizations for decompensation of HF, only few studies have evaluated the management of oral chronic therapies in the ADHF. More studies are needed for each single pharmacological class and their combination in this frequent clinical setting. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Nieminen MS, Harjola VP. Definition and epidemiology of acute heart failure syndromes. Am J Cardiol 2005;96(6A):5G–10G. [2] Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol 2014;63(12):1123–33. [3] Alla F, Zannad F, Filippatos G. Epidemiology of acute heart failure syndromes. Heart Fail Rev 2007;12(2):91–5. [4] McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33(14):1787–847. [5] Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29(19):2388–442. [6] Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemodynamic profiles that predict outcomes in patients admitted with heart failure. J Am Coll Cardiol 2003;41(10):1797–804 [21]. [7] Grady KL, Dracup K, Kennedy G, et al. Team management of patients with heart failure: a statement for healthcare professionals from the Cardiovascular Nursing Council of the American Heart Association. Circulation 2000;102(19):2443–56. [8] Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006;27(22):2725–36. [9] Maggioni AP, Dahlström U, Filippatos G, et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2013;15(7):808–17. [10] Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC. Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med 1985;102(3): 314–8. [11] Swedberg K. Beta-blockers in worsening heart failure: good or bad? Eur Heart J 2009;30:2177–9. [12] Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53: 557–73. [13] Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958–68. [14] Joseph SM, Cedars AM, Ewald GA, Geltman EM, Mann DL. Acute decompensated heart failure. Tex Heart Inst J 2009;36:510–20. [15] Stevenson LW, Massie BM, Francis GS. Optimizing therapy for complex or refractory heart failure: a management algorithm. Am Heart J 1998;135(6 Pt 2 Su):S293–309. [16] Shah MR, Hasselblad V, Stinnett SS, et al. Hemodynamic profiles of advanced heart failure: association with clinical characteristics and long-term outcomes. J Card Fail 2001;7(2):105–13.
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