**3.4 Inotropic agents**

134 Chronic Kidney Disease

Volume depletion increases the risk of significant renal dysfunction associated with ACE inhibitors and ARBs. Increases in creatinine of up to 30% are acceptable, and may identify a group of patients most likely to benefit from angiotensin inhibition (Koniari et al., 2010). HF patients who are unable to tolerate ACE inhibitor therapy because of hypotension, renal dysfunction, or hyperkalemia have a particularly high one-year mortality rate, in excess of

β-blockers are considered standard therapy in patients with HF and systolic dysfunction. They exert a number of beneficial effects, including prevention of ventricular arrhythmias, prevention of ventricular remodeling, reduction in myocardial oxygen demand, increased myocardial oxygen supply, and inhibition of other deleterious neurohormonal pathways. Their significant mortality benefit in patients with HF is well established through large clinical trials. Unfortunately, the majority of these studies excluded patients with significant renal dysfunction, but retrospective analyses of trials data have offered insight into the benefits in patients with mild-to-moderate renal impairment. COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study), for example, demonstrated a 35% reduction in the risk of death in patients with severe HF treated with carvedilol compared to placebo, but excluded patients with a serum creatinine greater than 2.8 mg/dL. Similarly, the CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial showed a 23% reduction in all-cause mortality in patients with EF ≤40% after myocardial infarction treated with carvedilol compared with placebo, but excluded patients with significant renal impairment (Dargie, 2001). A post-hoc analysis of individual patient data from these two trials, however, demonstrated that in patients with HF and mild-tomoderate CKD, carvedilol was safe and efficacious, associated with reductions in all-cause mortality, cardiovascular mortality, and HF hospitalization (Wali et al., 2011). CIBIS-II (The Cardiac Insufficiency Bisoprolol Study II) demonstrated a 34% reduction in mortality in patients with HF treated with bisoprolol compared to placebo, and excluded patients with serum creatinine ≥300 umol/L (3.4 mg/dL) (CIBIS-II Investigators and Committees, 1999). A post-hoc analysis of this trial showed that although patients with GFR <60 mL/min had higher overall mortality than those with GFR ≥60 mL/min, the benefit of bisoprolol was similar in both groups (Erdmann et al., 2001). The relative risk of mortality in the group with GFR <60 mL/min treated with bisoprolol compared to placebo was 0.66, and there was a non-significant trend towards an even greater benefit in the small number of patients with

An analysis of MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II), which demonstrated a 31% reduction in the risk of all-cause mortality with the addition of an implantable cardioverter-defibrillator to medical therapy in patients with ischemic cardiomyopathy and EF ≤30%, examined the predictors of sudden cardiac death (SCD) in the subset of patients in the medical arm of the study with impaired renal function, defined as GFR ≤75 mL/min. β-blocker therapy was a negative predictor of SCD, with a hazard ratio

Smaller studies have examined the benefits of β-blocker therapy in patients with end-stage renal failure. In a non-randomized study of 134 patients with HF and either chronic renal impairment, anemia, or both, treatment with β-blockers for 12 months was associated with

50% (Kittleson et al., 2003).

GFR <30 mL/min.

of 0.61 (Chonchol et al., 2007).

**3.3 -adrenergic receptor blockers** 

Inotropic medications such as dobutamine and milrinone are frequently used in patients with ADHF, particularly in the setting of the CRS where low cardiac output is felt to be a major contributor to rapidly declining renal function. Both agents are vasodilating inotropes, but they have different mechanisms of action. Dobutamine is an adrenergic agonist that affects inotropy and chronotropy via β-1 activity and peripheral vasodilation via β-2 activity. Milrinone is an inhibitor of type III phosphodiesterase and results in increased intracellular cyclic adenosine monophosphate (cAMP). This, in turn, results in increased inotropy (without chronotropy) as well as peripheral vasodilation. Although both agents have attractive hemodynamic profiles in the treatment of CRS, evidence suggests that they should not be part of standard therapy in this condition. OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) compared intravenous milrinone to placebo in patients with ADHF not requiring inotropic therapy for shock or other indications. There was no difference between the two groups in the primary endpoint of total number of days in hospital by 60 days after randomization. There was also no difference in the rate of progression of HF, but the patients treated with milrinone had higher rates of treatment failure, largely driven by higher rates of hypotension and atrial arrhythmias.

The ADHERE registry compared outcomes of patients with ADHF treated with vasodilating medications (nitroglycerin, nesiritide) and inotropic agents (dobutamine, milrinone). Even after adjustment for baseline variables including age, gender, blood pressure, BUN, creatinine, sodium, heart rate, and symptom severity, odds ratios for mortality between individual inotropes and individual vasodilators ranged from 1.45 to 2.17. Inotropic agents, therefore, are recommended by major society guidelines only for short-term use in patients with cardiogenic shock or refractory volume overload with diuretic resistance, and not recommended for routine use in hospitalized patients with ADHF. In addition, patients receiving these agents must be carefully monitored for hypotension and arrhythmias, and it should be recognized that the use of these agents is associated with a worse prognosis.

Dopamine is an endogenous catecholamine that binds dopamine receptors (D1-D5) as well as α and β adrenergic receptors with varying affinity depending on the dose administered. At low doses (2-5 mcg/kg/min), it primarily binds dopaminergic receptors and causes

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 137

mediate cardiac myocyte hypertrophy, vasoconstriction, and platelet aggregation. When AVP binds V2 receptors expressed in the renal collecting duct, the short-term result is increased translocation of vesicles containing aquaporin-2 (AQP2) water channels to the apical membrane of principal cells; in the long-term, AVP-V2 receptor binding results in the up-regulation of AQP2 protein expression. AQP2 mediates water transport across the apical membrane of the principal cell, resulting in urinary concentration and increased solute-free water retention (Schrier et al., 2009). AVP also stimulates urea reabsorption, resulting in an augmented medullary concentrating gradient and increased levels of blood urea nitrogen

In HF and CRS, low cardiac output causes nonosmotic AVP release, leading to inappropriate water retention. Low serum sodium and elevated blood urea nitrogen are strong predictors of mortality in HF, and both are mediated, at least in part, by AVP activity in the kidney. Augmentation of cardiac output with vasodilator medications is associated with reductions in plasma AVP (Bichet et al., 1986). Early studies demonstrated effective water removal without worsening renal function (Gheorghiade et al., 2007). Thus, the use of agents that interfere with AVP-mediated water retention has been an attractive concept in CRS. The SALT-1 and SALT-2 trials showed that tolvaptan, a selective oral V2 receptor antagonist, caused increases in serum sodium levels in patients with HF, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (Schrier et al., 2006). Unfortunately, the randomized EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial subsequently failed to demonstrate a mortality benefit or reduction in HF morbidity in patients hospitalized with HF treated with tolvaptan, despite sustained reductions in body weight with preserved renal function (Konstam et al., 2007). It seems, therefore, that vasopressin antagonists have little role in influencing clinical outcomes in patients hospitalized with HF and the CRS, although they may be useful in patients with hyponatremia that is difficult to manage with standard therapies. Additional studies are needed to further define the role of tolvaptan and other vasopressin antagonists

Adenosine is a purine nucleoside breakdown product of adenosine triphosphate. It interacts with four main receptor subtypes: A1, A2a, A2b, and A3. With the exception of coronary vasodilatation and increased renal medullary blood flow, its cardiovascular and renal effects are largely mediated via the A1 receptor. Binding of adenosine to A1 receptors in the heart results in slowing of the heart rate and decreased atrial contraction. In the kidney, adenosine is released from the macula densa in response to sodium delivery to the distal nephron via tubuloglomerular feedback (TGF). Adenosine released through TGF acts on local A1 receptors, causing afferent arteriolar vasoconstriction and reduction in GFR as well as increased proximal tubular sodium reabsorption. Blockade of these receptors should, therefore, result in improved renal blood flow and GFR and decreased sodium and water

In the setting of CRS, loop diuretics cause increased sodium delivery to the distal tubule, making the role of adenosine particularly relevant in this population. Animal studies showed that rolofylline, a selective A1 receptor antagonist, caused increased urine flow and urinary sodium excretion without increasing potassium excretion and without affecting

(Sands, 2003).

in the outpatient setting.

reabsorption.

**3.7 Adenosine antagonists** 

vasodilation of renal, splanchnic, cerebral, and coronary vessels. At higher doses, β adrenergic effects dominate, resulting in positive inotropy and chronotropy as well as β adrenergic-mediated vasodilation, with progressively increasing α adrenergic activity at still higher doses resulting in vasoconstriction.

For many years the use of "renal-dose" dopamine was advocated in acute renal failure, the rationale being that dopamine in doses up to 5 mcg/kg/min in animals and healthy volunteers resulted in increased renal blood flow and natriuresis via selective dopamine receptor binding. In recent years this approach has fallen out of favor, as multiple retrospective and small prospective studies failed to convincingly demonstrate any benefit in terms of renal function or survival. A meta-analysis of 61 trials comparing low-dose dopamine to placebo or no treatment found that dopamine was associated with a 24% increase in urine output on day 1 but was not associated with reductions in mortality, need for renal replacement therapy, or adverse events (Friedrich et al., 2005). Only one of the 61 studies included patients with HF, and this study did not assess mortality; only three of the studies included patients who were receiving diuretics. More recently, data from the DAD-HF (Dopamine in Acute Decompensated Heart Failure) trial has been presented, comparing low-dose dopamine plus low-dose furosemide to high-dose furosemide alone in patients with ADHF. The two regimens were not associated with statistically significant rates of diuresis, but the patients receiving dopamine plus low-dose furosemide were less likely to develop worsening renal function (36% and 4% of patients in dopamine/furosemide and furosemide only groups, respectively, had >25% increase in serum creatinine). As more data become available regarding outcomes with low-dose dopamine in this specific population, "renal-dose" dopamine may turn out to be useful after all.

#### **3.5 Vasodilators**

Nesiritide, a synthetic B-type natriuretic peptide (BNP), has been used in the management of ADHF, particularly in patients at risk for worsening renal function with standard therapies. Like naturally occurring BNP, released from ventricular myocardium under conditions of increased wall stress, nesiritide is a vasodilator, causing both arterial and venous dilatation as well as mild diuresis. Its rapid onset of action, apparent neurohormonal benefits, and lack of need for invasive hemodynamic monitoring led to much initial enthusiasm for its use in ADHF, as well as FDA approval for this indication (Publication Committee for the VMAC Investigators, 2002). Use of this agent took a sharp decline, however, after meta-analyses suggested increased 30-day mortality and increased risk of renal failure with nesiritide (Hauptman et al., 2006; Sackner-Bernstein et al., 2005a; 2005b). The definitive randomized clinical trial, ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure), recently demonstrated that while nesiritide is safe with no increased risk of 30-day death or hospitalization or increased risk of renal failure, it offers no significant clinical benefit when added to standard therapy in patients with ADHF (Hernandez, 2010).

#### **3.6 Vasopressin antagonists**

Arginine vasopressin (AVP), a nonapeptide synthesized by the hypothalamus and released by the posterior pituitary gland in response to increased plasma osmolality or decreased plasma volume, binds to 3 distinct receptor subtypes (V1a, V1b, and V2). V1 receptors

vasodilation of renal, splanchnic, cerebral, and coronary vessels. At higher doses, β adrenergic effects dominate, resulting in positive inotropy and chronotropy as well as β adrenergic-mediated vasodilation, with progressively increasing α adrenergic activity at still

For many years the use of "renal-dose" dopamine was advocated in acute renal failure, the rationale being that dopamine in doses up to 5 mcg/kg/min in animals and healthy volunteers resulted in increased renal blood flow and natriuresis via selective dopamine receptor binding. In recent years this approach has fallen out of favor, as multiple retrospective and small prospective studies failed to convincingly demonstrate any benefit in terms of renal function or survival. A meta-analysis of 61 trials comparing low-dose dopamine to placebo or no treatment found that dopamine was associated with a 24% increase in urine output on day 1 but was not associated with reductions in mortality, need for renal replacement therapy, or adverse events (Friedrich et al., 2005). Only one of the 61 studies included patients with HF, and this study did not assess mortality; only three of the studies included patients who were receiving diuretics. More recently, data from the DAD-HF (Dopamine in Acute Decompensated Heart Failure) trial has been presented, comparing low-dose dopamine plus low-dose furosemide to high-dose furosemide alone in patients with ADHF. The two regimens were not associated with statistically significant rates of diuresis, but the patients receiving dopamine plus low-dose furosemide were less likely to develop worsening renal function (36% and 4% of patients in dopamine/furosemide and furosemide only groups, respectively, had >25% increase in serum creatinine). As more data become available regarding outcomes with low-dose dopamine in this specific population,

Nesiritide, a synthetic B-type natriuretic peptide (BNP), has been used in the management of ADHF, particularly in patients at risk for worsening renal function with standard therapies. Like naturally occurring BNP, released from ventricular myocardium under conditions of increased wall stress, nesiritide is a vasodilator, causing both arterial and venous dilatation as well as mild diuresis. Its rapid onset of action, apparent neurohormonal benefits, and lack of need for invasive hemodynamic monitoring led to much initial enthusiasm for its use in ADHF, as well as FDA approval for this indication (Publication Committee for the VMAC Investigators, 2002). Use of this agent took a sharp decline, however, after meta-analyses suggested increased 30-day mortality and increased risk of renal failure with nesiritide (Hauptman et al., 2006; Sackner-Bernstein et al., 2005a; 2005b). The definitive randomized clinical trial, ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure), recently demonstrated that while nesiritide is safe with no increased risk of 30-day death or hospitalization or increased risk of renal failure, it offers no significant clinical benefit when added to standard therapy in patients with ADHF

Arginine vasopressin (AVP), a nonapeptide synthesized by the hypothalamus and released by the posterior pituitary gland in response to increased plasma osmolality or decreased plasma volume, binds to 3 distinct receptor subtypes (V1a, V1b, and V2). V1 receptors

higher doses resulting in vasoconstriction.

"renal-dose" dopamine may turn out to be useful after all.

**3.5 Vasodilators** 

(Hernandez, 2010).

**3.6 Vasopressin antagonists** 

mediate cardiac myocyte hypertrophy, vasoconstriction, and platelet aggregation. When AVP binds V2 receptors expressed in the renal collecting duct, the short-term result is increased translocation of vesicles containing aquaporin-2 (AQP2) water channels to the apical membrane of principal cells; in the long-term, AVP-V2 receptor binding results in the up-regulation of AQP2 protein expression. AQP2 mediates water transport across the apical membrane of the principal cell, resulting in urinary concentration and increased solute-free water retention (Schrier et al., 2009). AVP also stimulates urea reabsorption, resulting in an augmented medullary concentrating gradient and increased levels of blood urea nitrogen (Sands, 2003).

In HF and CRS, low cardiac output causes nonosmotic AVP release, leading to inappropriate water retention. Low serum sodium and elevated blood urea nitrogen are strong predictors of mortality in HF, and both are mediated, at least in part, by AVP activity in the kidney. Augmentation of cardiac output with vasodilator medications is associated with reductions in plasma AVP (Bichet et al., 1986). Early studies demonstrated effective water removal without worsening renal function (Gheorghiade et al., 2007). Thus, the use of agents that interfere with AVP-mediated water retention has been an attractive concept in CRS. The SALT-1 and SALT-2 trials showed that tolvaptan, a selective oral V2 receptor antagonist, caused increases in serum sodium levels in patients with HF, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (Schrier et al., 2006). Unfortunately, the randomized EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial subsequently failed to demonstrate a mortality benefit or reduction in HF morbidity in patients hospitalized with HF treated with tolvaptan, despite sustained reductions in body weight with preserved renal function (Konstam et al., 2007). It seems, therefore, that vasopressin antagonists have little role in influencing clinical outcomes in patients hospitalized with HF and the CRS, although they may be useful in patients with hyponatremia that is difficult to manage with standard therapies. Additional studies are needed to further define the role of tolvaptan and other vasopressin antagonists in the outpatient setting.

#### **3.7 Adenosine antagonists**

Adenosine is a purine nucleoside breakdown product of adenosine triphosphate. It interacts with four main receptor subtypes: A1, A2a, A2b, and A3. With the exception of coronary vasodilatation and increased renal medullary blood flow, its cardiovascular and renal effects are largely mediated via the A1 receptor. Binding of adenosine to A1 receptors in the heart results in slowing of the heart rate and decreased atrial contraction. In the kidney, adenosine is released from the macula densa in response to sodium delivery to the distal nephron via tubuloglomerular feedback (TGF). Adenosine released through TGF acts on local A1 receptors, causing afferent arteriolar vasoconstriction and reduction in GFR as well as increased proximal tubular sodium reabsorption. Blockade of these receptors should, therefore, result in improved renal blood flow and GFR and decreased sodium and water reabsorption.

In the setting of CRS, loop diuretics cause increased sodium delivery to the distal tubule, making the role of adenosine particularly relevant in this population. Animal studies showed that rolofylline, a selective A1 receptor antagonist, caused increased urine flow and urinary sodium excretion without increasing potassium excretion and without affecting

seen.

to the removal of isotonic fluid.

**3.9 Erythropoietin and correction of anemia** 

the CRS population.

management of the CRS.

**4. Conclusions and future directions** 

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 139

ultrafiltration group than in the IV diuretic group. No differences in renal outcomes were

Ultrafiltration can be performed via peripheral or central veins, with rates of fluid removal regulated by a hematocrit sensor and ranging from 10 to 500 mL per hour. Blood flow rates range from 10 to 40 mL per minute, and total extracorporeal blood volume can be as low as 33 mL. Maintenance of a constant hematocrit ensures that the rate of fluid removal from the intravascular compartment is equivalent to the rate of fluid shift from the extravascular to intravascular compartments. Low extracorporeal blood volume and slow fluid removal minimize neurohormonal activation and prevent hypotension. In contrast to the hypotonic fluid removal that occurs with diuresis, ultrafiltration removes isotonic fluid, potentially resulting in greater total sodium removal. The mechanism of the sustained benefit seen in the UNLOAD trial is thought to be related to the attenuation of neurohormonal activity and

The major limitation to the widespread use of ultrafiltration in HF and the CRS is likely to be the cost of the filters used. In addition, questions remain about patient selection, optimal timing of initiation of therapy, and determination of total fluid volume to be removed. The specific role of ultrafiltration in patients who develop worsening renal function with diuretic therapy is being investigated in CARESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure), and will help to define the role of this therapy specifically in

Anemia is common in both HF and CKD, and the term "cardiorenal-anemia syndrome" refers to the coexistence of anemia and the CRS. EPO is widely used in the CKD population to correct anemia to a moderate degree. Studies in this population have shown improved parameters of cardiac performance with EPO therapy, including reduction of left ventricular hypertrophy and dilatation, improved left ventricular ejection fraction, and increased cardiac output (Linde et al., 1996; Low et al., 1989; Low-Friedrich et al., 1991). Studies of EPO and iron administration to patients with HF with or without CKD have shown inconsistent results, but some studies have demonstrated modest improvements in symptoms and functional capacity as well as renal function, ejection fraction, and left ventricular dimensions (Bolger et al., 2006; Palazzuoli et al., 2006; Silverberg et al., 2000; Toblli et al., 2007). The FAIR-HF (Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency) study demonstrated improved symptoms and functional capacity in patients with HF and iron deficiency, even in the absence of overt anemia, treated with intravenous iron as compared to placebo (Anker et al., 2009). The ongoing IRON-HF (Iron Supplementation in Heart Failure Patients With Anemia) and RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure ) studies will likely further clarify the role of iron and EPO therapies in patients with HF and provide additional insights into the

The Cardiorenal Syndrome is a pathophysiologic state involving complex feedback processes between the failing heart and failing kidneys, and is associated with a

either blood pressure or renal function, and protected against nephrotoxic medicationinduced acute renal failure (Nagashima & Karasawa, 1996; Yao et al., 1994). A small clinical study supported this, demonstrating that the addition of rolofylline to diuretics in patients with volume overload and renal impairment resulted in an improvement in renal function and increased diuresis with reduced diuretic requirements (Givertz et al., 2007). Unfortunately, the PROTECT (Placebo-Controlled Randomized Study of the Selective A₁ Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study, which randomized 2033 patients with ADHF to intravenous rolofylline or placebo, failed to demonstrated any difference between groups in the primary endpoint of treatment success (moderate or marked improvement in dyspnea at 24 and 48 hours without treatment failure), treatment failure (death or readmission for HF by 7 days, persistent worsening renal failure, or worsening HF), or no change (Massie et al., 2010). There were no differences in the number of patients who developed renal impairment or in the secondary endpoint of death or rehospitalization for cardiac or renal causes at 60 days. The overall adverse event rates were similar between groups, although more patients in the rolofylline group had seizures, a known side effect of A1 antagonists mediated via central nervous system A1 receptors that regulate electrical excitability. Based on the lack of clinical efficacy, coupled with the increased risk of seizures, rolofylline is not recommended for the treatment of CRS.

Another intravenous selective A1 antagonist, tonapofylline, was also investigated in Phase II clinical trials after preclinical studies and small human studies suggested effective natriuresis. The TRIDENT-1 (Safety and Tolerability of IV Tonapofylline in Subjects With Acute Decompensated Heart Failure and Renal Insufficiency) and POSEIDON (Oral BG9928 in Patients with Heart Failure and Renal Insufficiency) trials were both terminated early after review of interim safety data from TRIDENT-1 revealed that two patients in the tonapofylline group had had seizures (Ensor & Russell, 2010). Of note, seizures were not reported in studies of oral tonapofylline, and in rat studies, tonapofylline did not cross the blood-brain barrier (Ensor & Russell, 2010). There is insufficient data to determine whether oral formulations of A1 antagonists are safe or clinically useful.

#### **3.8 Ultrafiltration**

Extracorporeal fluid removal has been used for decades in ADHF, typically reserved for patients with fluid overload states that are refractory to diuretics and other medical therapies. Small studies of ultrafiltration in HF have previously demonstrated effective fluid removal, rapid symptom improvement, attenuated neurohormonal activity, and hemodynamic improvements including reduced LV filling pressures and reduced pulmonary arterial pressures without reductions in systemic blood pressure or cardiac index (Marenzi et al., 1993; Rimondini et al., 1987). The landmark UNLOAD (Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure) trial randomized 200 patients with ADHF and volume overload to veno-venous ultrafiltration or intravenous diuretics (Costanzo et al., 2005). Patients in both groups had similar improvements in dyspnea scores, but the patients in the ultrafiltration group had greater weight loss and net fluid loss at 48 hours. Importantly, there were fewer rehospitalizations, rehospitalization days, and unscheduled clinic visits at 90 days in the

either blood pressure or renal function, and protected against nephrotoxic medicationinduced acute renal failure (Nagashima & Karasawa, 1996; Yao et al., 1994). A small clinical study supported this, demonstrating that the addition of rolofylline to diuretics in patients with volume overload and renal impairment resulted in an improvement in renal function and increased diuresis with reduced diuretic requirements (Givertz et al., 2007). Unfortunately, the PROTECT (Placebo-Controlled Randomized Study of the Selective A₁ Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study, which randomized 2033 patients with ADHF to intravenous rolofylline or placebo, failed to demonstrated any difference between groups in the primary endpoint of treatment success (moderate or marked improvement in dyspnea at 24 and 48 hours without treatment failure), treatment failure (death or readmission for HF by 7 days, persistent worsening renal failure, or worsening HF), or no change (Massie et al., 2010). There were no differences in the number of patients who developed renal impairment or in the secondary endpoint of death or rehospitalization for cardiac or renal causes at 60 days. The overall adverse event rates were similar between groups, although more patients in the rolofylline group had seizures, a known side effect of A1 antagonists mediated via central nervous system A1 receptors that regulate electrical excitability. Based on the lack of clinical efficacy, coupled with the increased risk of seizures, rolofylline is not recommended

Another intravenous selective A1 antagonist, tonapofylline, was also investigated in Phase II clinical trials after preclinical studies and small human studies suggested effective natriuresis. The TRIDENT-1 (Safety and Tolerability of IV Tonapofylline in Subjects With Acute Decompensated Heart Failure and Renal Insufficiency) and POSEIDON (Oral BG9928 in Patients with Heart Failure and Renal Insufficiency) trials were both terminated early after review of interim safety data from TRIDENT-1 revealed that two patients in the tonapofylline group had had seizures (Ensor & Russell, 2010). Of note, seizures were not reported in studies of oral tonapofylline, and in rat studies, tonapofylline did not cross the blood-brain barrier (Ensor & Russell, 2010). There is insufficient data to determine whether

Extracorporeal fluid removal has been used for decades in ADHF, typically reserved for patients with fluid overload states that are refractory to diuretics and other medical therapies. Small studies of ultrafiltration in HF have previously demonstrated effective fluid removal, rapid symptom improvement, attenuated neurohormonal activity, and hemodynamic improvements including reduced LV filling pressures and reduced pulmonary arterial pressures without reductions in systemic blood pressure or cardiac index (Marenzi et al., 1993; Rimondini et al., 1987). The landmark UNLOAD (Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure) trial randomized 200 patients with ADHF and volume overload to veno-venous ultrafiltration or intravenous diuretics (Costanzo et al., 2005). Patients in both groups had similar improvements in dyspnea scores, but the patients in the ultrafiltration group had greater weight loss and net fluid loss at 48 hours. Importantly, there were fewer rehospitalizations, rehospitalization days, and unscheduled clinic visits at 90 days in the

oral formulations of A1 antagonists are safe or clinically useful.

for the treatment of CRS.

**3.8 Ultrafiltration** 

ultrafiltration group than in the IV diuretic group. No differences in renal outcomes were seen.

Ultrafiltration can be performed via peripheral or central veins, with rates of fluid removal regulated by a hematocrit sensor and ranging from 10 to 500 mL per hour. Blood flow rates range from 10 to 40 mL per minute, and total extracorporeal blood volume can be as low as 33 mL. Maintenance of a constant hematocrit ensures that the rate of fluid removal from the intravascular compartment is equivalent to the rate of fluid shift from the extravascular to intravascular compartments. Low extracorporeal blood volume and slow fluid removal minimize neurohormonal activation and prevent hypotension. In contrast to the hypotonic fluid removal that occurs with diuresis, ultrafiltration removes isotonic fluid, potentially resulting in greater total sodium removal. The mechanism of the sustained benefit seen in the UNLOAD trial is thought to be related to the attenuation of neurohormonal activity and to the removal of isotonic fluid.

The major limitation to the widespread use of ultrafiltration in HF and the CRS is likely to be the cost of the filters used. In addition, questions remain about patient selection, optimal timing of initiation of therapy, and determination of total fluid volume to be removed. The specific role of ultrafiltration in patients who develop worsening renal function with diuretic therapy is being investigated in CARESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure), and will help to define the role of this therapy specifically in the CRS population.
