Hospitalization for acute decompensated

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1 Management of acute decompensated heart failure in an evidence-based era: What is the evidence behind the current standard of care? Wassim H. Fares, MD Despite the increased mortality and morbidity in patients with acute decompensated heart failure (ADHF), its management has been based primarily on anecdotal experiences and physiologic assumptions rather than on prospective randomized controlled trials. The data on diuretics have been conflicting. Routine use of inotropes in ADHF has been clearly associated with increased mortality and morbidity, although inotropes seem to cause short-term clinical improvement. The safety of the different vasoactive medications has never been adequately confirmed in prospective trials despite their use for a long time in heart failure. Good evidence that supports the safety and efficacy of the different medications that are routinely used in ADHF is lacking. Unless properly designed prospective clinical trials are done to evaluate the safety of the various ADHF regimens, clinicians might continue to be misguided by the beneficial short-term effects at the expense of long-term mortality and morbidity. (Heart Lung 2008; 37: ) Hospitalization for acute decompensated heart failure (ADHF), sometimes referred to as acute heart failure (HF), acute vascular failure, or exacerbation or worsening of HF, constitutes the most common cause of hospitalization in the United States and Europe. 1,2 Hospitalizations typically have enormous impact on the physical, mental, and financial situation of patients and their families. HF has an average in-hospital mortality rate of 4% to 5%, a 1-month posthospitalization mortality rate of 7% to 11%, and a 1-year posthospitalization mortality rate of 33%. 3 This is in comparison with an annual mortality rate of 7% for nonhospitalized patients in New York Heart Association class II and 12% for patients in New York Heart Association class III. 4 HF is the only cardiac condition associated with an increasing mortality rate. 3,4 Despite the high mortality rate for this syndrome, few studies have been performed in the setting of ADHF, partly because of the difficulty recruiting and From the Department of General Internal Medicine, Cleveland Clinic, Cleveland, Ohio. Conflict of interest: None. Corresponding author: Wassim H. Fares, MD, Department of General Internal Medicine, Section of Hospital Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH /$ see front matter Copyright 2008 by Mosby, Inc. doi: /j.hrtlng designing trials that involve patients in acute decompensation, 5 the heterogeneity of the population with ADHF, 6 and the lack of consensus on meaningful clinical end points, such as improvement of dyspnea. 6 This is clearly evidenced by the paucity of evidence A level recommendations in the European Society of Cardiology guidelines on the diagnosis and treatment of ADHF. 7 Only 15% of all recommendations in these guidelines were of evidence A level, whereas 56% were of evidence C level. This is also manifested in the Heart Failure Society of America 2006 comprehensive HF practice guidelines 8 in which 88% of all recommendations in the ADHF section were of evidence C level. A cascade of neurohormonal and cellular changes is at the core of the pathophysiology of HF (Figure 1). Most notable is the activation of the renin-angiotensin-aldosterone-system (RAAS) and the sympathetic nervous system (SNS), which initiates a vicious cycle of pathologic changes. 9 The release of endothelin-1, inflammatory cytokines (eg, interleukin-6 and tumor necrosis factor- ), and hormones (eg, arginine vasopressin) is an integral part of this cycle that collectively leads to vasoconstriction and fluid and sodium retention. These maladaptive pathways also lead to endothelial dysfunction, increased thrombotic state, and hypertrophy of both myocardial and vascular smooth muscle cells. HEART & LUNG VOL. 37, NO

2 Management of acute decompensated heart failure Fares Fig 1 Effects of commonly used drugs in ADHF. Favorable action (thick arrows); unfavorable action (thin arrows). Table I Acute decompensated heart failure medications Diuretics Drug Action Adverse effects Decrease Pulmonary edema Activate RAAS and SNS, worsen kidney function, and potentially decrease survival Inotropes Improve cardiac output Arrhythmogenic and increase mortality Vasoactive Venodilator and/or medications arteriodilator May increase neurohormonal activation and worsen mortality Evidence of safety in ADHF None None None RAAS, Renin angiotensin aldosterone system; SNS, sympathetic nervous system; ADHF, acute decompensated heart failure. Commonly used ADHF medications, their actions, adverse effects, and evidence of safety in ADHF. Subsequently, renal function deteriorates directly because of the effect of these neurohormonal and inflammatory changes or indirectly because of renal hypoperfusion that results from decreased cardiac output and/or vascular changes. Either way, this ensuing renal dysfunction results in further activation of RAAS and SNS. This complex interaction of structural, functional, cellular, genetic, neurohormonal, and inflammatory factors, which are yet to be fully understood, makes it challenging to find drug options that have both short- and long-term benefits (Table I). For example, inotrope use in the ADHF setting is known to cause short-term clinical and hemodynamic improvements (Figure 1) but proved to have a negative long-term mortality impact This might in part be due to subclinical ischemia that is associated with ADHF, as evidenced by a mild elevation in troponin levels and increased platelet activation. 16 This makes ADHF comparable to acute coronary syndrome because of its high mortality and morbidity and not just a simple exacerbation of chronic HF, as perceived by many. This article reviews the evidence behind the current standard-of-care management of patients hospitalized with ADHF. LOOP DIURETICS Loop diuretics are the most commonly used drug in HF. 17 They have long been known to reduce body fluid volume and thus decrease pulmonary edema 18 (Table II) by inhibiting the reabsorption of sodium and chloride in the ascending limb of the Loop of Henle. There has not been any randomized controlled trial (RCT) to date that has evaluated the safety of loop diuretic use in ADHF. There have been MAY/JUNE 2008 HEART & LUNG

3 Fares Management of acute decompensated heart failure Table II Drugs used in acute decompensated heart failure and their hemodynamic effects PCWP SBP PVR SVR CI Heart rate Furosemide / Dobutamine 2 2 _ 1 Milrinone _ 1 Nesiritide Nitroprusside Nitroglycerin PCWP, Pulmonary capillary wedge pressure; SBP, systolic blood pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; CI, cardiac index. some retrospective reports of worsening renal function, pathologic neurohormonal changes, and increased mortality associated with the use of diuretics in patients with HF This is believed to be in part due to the stimulation of the SNS and RAAS systems in response to volume depletion. 21 The activation of these systems leads to pathologic vascular and ventricular remodeling. 22 However, a recent Cochrane meta-analysis that included 14 small chronic HF trials (N 525) with follow-up periods ranging from 4 to 24 weeks suggested a lower mortality rate and less worsening of HF associated with the use of diuretics. 23 This suggests that the increased use of diuretics may have been a marker of worse HF rather than a cause of worsening HF. Although loop diuretics are most commonly administered as intravenous boluses, the use of a continuous intravenous diuretic infusion 24,25 was supported by a recent Cochrane review that suggested greater diuresis and improved safety compared with conventional bolus administration. 26 Another common practice relating to loop diuretic use in ADHF that lacks literature support is the addition of a second diuretic, such as hydrochlorothiazide or metolazone, to the loop diuretic, which is believed to overcome diuretic resistance. INOTROPES Because of increasing myocardial contractility and thus cardiac output (Table II), inotropes (some of which are referred to as inodilators because of their simultaneous vasodilator effects) have long been used to augment diuresis and end-organ perfusion, thus reversing the decompensation of HF. However, there is little evidence guiding inotrope use in ADHF, and this evidence shows increased morbidity, such as arrhythmogenicity 27 and mortality associated with inotrope use. Dobutamine, which stimulates both beta-1 and beta-2 receptors and is among the most commonly used inotropes in ADHF, was noted to be associated with a worse in-hospital mortality rate in the Acute Decompensated Heart Failure National Registry (ADHERE) 28,29 and a worse 6-month mortality rate in the Calcium Sensitizer or Inotrope or None in Low Output Heart Failure Study (CASINO) (which randomized patients with ADHF to receive dobutamine, levosimendan, or placebo) 14,15,30 and other observational studies. 10,12,13,16,31 In an experimental setting, dobutamine had detrimental effects on the hibernating myocardium by causing elevation of troponin levels and myocyte necrosis, which is believed to be mediated in part by increasing oxygen demand and thus myocyte apoptosis. 32,33 This is clinically significant because approximately one third of patients with worsening HF have hibernating myocardium that may be caused by chronic ischemia and/or neurohormonal changes that occur in the setting of HF. 34,35 The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure trial (OPTIME-CHF) is one of the few RCTs that studied patients with ADHF. 11 A total of 951 patients were randomized to receive either milrinone, which is a phosphodiesterase inhibitor, or placebo. There was a nonsignificant trend toward an increased mortality rate associated with milrinone treatment and a significant increase in hypotension and atrial fibrillation. Observational data also showed an increased hospitalization and mortality risk associated with the use of milrinone in patients HEART & LUNG VOL. 37, NO

4 Management of acute decompensated heart failure Fares with HF. 28,36 Similarly, dopamine lacks any safety data in the ADHF setting. VASOACTIVE MEDICATIONS Vasoactive medications are commonly used in ADHF to decrease afterload and/or preload and thus improve ventricular filling pressures and cardiac output (Table II). One of the medications that recently caused controversy in HF management is nesiritide, a recombinant form of the human B- type natriuretic peptide. Although nine RCTs using nesiritide have been published, with a combined total of 1769 patients, its clinical role has not been settled. 27,37-43 This lack of consensus is mainly attributed to the heterogeneity between these RCTs and the use of higher than the eventual Food and Drug Administration-approved dose of nesiritide in the earlier trials. The only two trials that used the Food and Drug Administration-approved dose of nesiritide, Vasodilatation in the Management of Acute CHF (VMAC) and PROACTION (N 726), showed clinical and hemodynamic improvement 41,43 ; however, unadjusted meta-analysis of selected trials showed increases in kidney dysfunction and mortality rate, although neither reached statistical significance After these concerns with the use of nesiritide were raised, a cardiology expert panel, chaired by Eugene Braunwald, MD, provided specific recommendations to guide the use of nesiritide in ADHF. The recommendations state that nesiritide should not be used for intermittent outpatient infusion, for scheduled repetitive use, to improve renal function, or to enhance diuresis. 47 Other vasoactive medications used in ADHF are nitroglycerin and nitroprusside. The concern with nitroprusside, despite being an effective blood pressure-lowering drug, has always been the requirement for close monitoring and thiocyanate toxicity, which is commonly associated with prolonged use, liver disease, and renal failure. That is why nitroprusside is rarely used in ADHF, 17 and when it is used, it is usually given to those with severely low output and hypertensive HF. 7 Its effect on mortality has never been prospectively studied. Along the same lines, nitroglycerin is effective in relief of symptoms from pulmonary edema. However, its use in ADHF lacks clear evidence of safety in clinical trials, although there has been a suggestion that its use is not correlated with worsening renal function. 41 It was used as the control agent in VMAC, which had a 30-day mortality rate of 5.1% versus 8.1% in the nesiritide group (P.5). 41 Both nitroprusside and nitroglycerin are converted to nitric oxide, which has a direct effect on arterial and venous smooth muscle causing arteriodilation and venodilation, respectively. The main limitation of nitroglycerin use is the development of tolerance to its hemodynamic effect. WHAT TO DO WITH THE HOME REGIMEN AT THE TIME OF ADMISSION? There are no RCTs to answer this question for any of the HF medications. Although some experts recommend stopping or decreasing the dose of ACEI while administering intravenous diuretics, others recommend stopping ACEI only in the event of an increasing creatinine level. There are no data on what to do with the beta-blocker dose on hospitalization for ADHF; however, the consensus is to stop the beta-blocker in patients in shock, decrease the dose in hypotensive patients, and continue the same dose in everybody else. 48 Although digoxin has been used in HF for hundreds of years, no RCT has ever studied it in the setting of ADHF. Intravenous digoxin was shown to have favorable effects on central hemodynamics and neurohormonal changes in the setting of severe HF but was not studied in ADHF, and thus it should not be used intravenously in patients with ADHF. 49 CONCLUSIONS There is little evidence supporting the safety or efficacy of the drugs that we use as standard-ofcare management for patients with ADHF. Most of what we, as clinicians, do to care for our patients with ADHF is primarily based on historical practices and theoretic physiologic changes that may not always correlate with morbidity or mortality benefit. Emerging data are leading us to question traditional therapeutic approaches. Among many other studies, OPTIME-CHF, PROACTION, VMAC, and EVEREST 50 proved to us that it is not impossible to recruit patients with ADHF into well-designed RCTs. Unless this field is actively researched in prospective randomized trials, there is little we can do to help the tens of millions who are admitted annually to hospitals worldwide with worsening HF. REFERENCES 1. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics 2006 update: a report from the American MAY/JUNE 2008 HEART & LUNG

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