Disclosure Information: clinical research grants from: BMS, Bayer Jose López-Sendón Hospital Universitario La Paz. Madrid Antagonistas del receptor A1 de Adenosina Nuevo pardigma en el tratamiento de la insuficiencia cardiaca aguda

The old times. Heart failure as a congestive syndrome

Adams KF et al. Am Heart J. 2005; 149: 209 Cleland JGF et al. Eur Heart J. 2003; 24: 442 Fonarow GC et al. J Am Coll Cardiol. 2005; 45: 345A Hospitalizations for HF: Patient Characteristics ADHERE EURO HF OPTIMIZE-HF (%) (107,920 pts.) (11,327 pts.) (48,612 pts.) Any dyspnea 89 70 90? Dyspnea at rest 34 40 45 Fatigue 32 35 23 Rales 68 N/A 65 Peripheral edema 66 23 65

60-Day All-cause Mortality 0% 10% 20% N = 204 115 (64%) (36%) ACTIVE in CHF Adapted from Gheorghiade M et al. JAMA. 2004;291:1963 Congestion after Initial In-Hospital Therapy is Associated with Higher 60-day Mortality Severe Congestion* 7.8 3.5 No Severe Congestion*

Bayliss et al. Br Heart J. 1987; 57: 17 Neurohormonal effect of Diuretics in Heart Failure Basal (n=12) Plasma Renin Activity (ng/mL/h) 50 10 2.5 0.5 P =.0002 After Diur étic (n=11) Plasma Aldosterone (pmol/L) % 1000 600 200 100 P =.0007 Basal (n=12) After Diuretic (n=11)

Resistencia a diuréticos Incremento de la Mortalidad y Morbilidad Tratamiento diur ético Insuficiencia renal Disminuci ón de la función renal Desarrollo de Resistencia a Diur éticos Disminuci ón Flujo sanguíneo Activaci ón Neurohormonal

Incidencia de Insuf. Renal en Insf. Cardiaca 13 10 4 12 9 6 41 21 16 27 1.8 30 0 5 10 15 20 25 30 35 ADHERE OSCUR internista OSCUR cardiologo HGM cardiologo ICCAR ambulatorio EHFS-1 Rusia EHFS 1 Holanda EHFS-1 España EHFS-1 Media EVEREST VALIANT MADIT 2 Registros Ensayos cl ínicos % EHFS-2 ICC EHFS-2 ICA 21 11 0 5 10 15 20 25 30 35

Incidencia de IR en IC 43,3% 41,8% Pacientes (nº) FEVI ≥ 50% FEVI < 50% Insuficiencia Renal: TFG < 60 ml/min/1.73m2 Grigorian L, et al . REC 2006:59:99

Insuficiencia cardiaca aguda Factores relacionados con Mortalidad intrahospitalaria EHFS-II: n=3432 L ó pez-Send ón et al ECC 2007

Función Renal y Pron óstico FEVI ≥ 50% FEVI < 50% Grigorian L, et al . REC 2006:59:99 TFG < 30 TFG < 30 TFG 30-60 TFG 30-60 TFG > 60 TFG > 60 RR (ajustado) TFG<30/>60 : 2.86; p=0.021 RR (ajustado) TFG<30/>60 : 3.79; p=0.011 RR (ajustado) TFG 30-60/>60 : 1.44; p=NS RR (ajustado) TFG 30-60/>60 : 1.02; p=NS

NA + and H 2 O RETENTION SNS 1 Efferent art. constriction 2 Na + reabs. in prox. tubule Angiotensin 1 Efferent art. constriction 2 Na + reabs. in prox. tubule Aldosterone 3 Reabsorption H 2 O and Na+ 4 K + Secretion Vasopressin 5 H 2 O reabs. in collecting tubule 6 Na + reabs. in ascending branch of the loop of Henle Adenosin 1b A fferent art. constriction 1 Na + reabs. in prox. tubule Atrial Natriuretic P 7 Increase glomerular filtration 8 Na reabs. in collecting tubule Renal Prostaglandins 9 Afferent art. vasodilatation 10 Reduce Na + reabsorption in asc. branch of loop of Henle 11 Inhibit Na + reabsorption in collecting tubule 12 1 2 4 5 6 7 8 9 10 3 1b

New Diuretics ? • BNP • Endotelin antagonists • Adenosin receptor inh. • Vasopresin antagonists • Aldosterone inhibitors

Adenosin A1 Receptors Reabsorción de Na+ Vasoconstricción Adenosin A1 receptors: Afferent arteriolar vasodilatation Inhibit Na + reabsorption in the proximal tubule and enhance diuresis Block adenosine-mediated tubo-glomerular feedback .

Adenosine A1 receptor antagonists Adenosine-mediated tubo-glomerular feedback The macula densa mechanism by which increased Na + delivery in the proximal tubule leads to a decrease in GFR

Adenosine-mediated tubo-glomerular feedback

The macula densa mechanism by which increased Na + delivery in the proximal tubule leads to a decrease in GFR

A1 receptor Blockers Rolofillyne (KW-3902) BG9928 BG9719 (CVT-124) SLV320

BG9719, an A1R antagonist, protects against the decline in renal function observed with diuretic therapy n = 63, NYHA class II-IV, EF ï‚£ 40% and edema despite furosemide (80 mg/d) IV BG9928 (3, 15, 75 y 225 mg) vs placebo for 10 days BG9719 increased urine output, sodium excretion and GFR Furosemide increased urine output at the expense of decreased GFR BG9719 plus furosemide increased diuresis without deterioration in GFR Decrease in body weight of 0.6 kg (0.3 kg with placebo) Gottlieb et al. JACC 2000;35:56-59

CKI-201 - ADHF patients with renal impairment Cumulative Urine Volume and daily dose of i.v. furosemide Day 1 Day 2 Day 3 0 40 80 120 160 * Daily dose of i.v. Furosemide (mg) * P < 0.05 vs. placebo). Givertz et al. JACC 2007; 50:1551-1560 By day 4 or day of discharge if earlier, i.v. furosemide administration tended to be lower in the KW-3902 group Placebo 2.5 mg 30 mg 60 mg 15 mg

CKI-202 – ADHF patients refractory to diuretics Hourly Urine Volume and Creatinine Clearance (34 ml/min) * P < 0.05 vs. placebo Givertz et al. JACC 2007; 50:1551-1560 Enhances the response to loop diuretics and may have a renal protective effect I ncrease Na + excretion that with &quot;little kaliuresis“ Decreases BW, improves dyspnea and edemas No change in morbidity and mortality for worsening of HF

Pilot study 301 patients Barry M. Massie For the PROTECT Investigators and Coordinators

PROTECT Studies: Primary Endpoint Treatment success on days 2 and 3 Dyspnea reported by the patient as moderately or markedly better compared to study start; and not a treatment failure Treatment failure (includes any 1 of the following criteria) Death or readmission for heart failure through Day 7 Worsening symptoms and/or signs of heart failure Persistent renal impairment (serum creatinine increases ≥0.3 mg/dL at Day 7, confirmed at Day 14). Patient unchanged Neither treatment success or treatment failure

Treatment success on days 2 and 3

Dyspnea reported by the patient as moderately or markedly better compared to study start; and not a treatment failure

Treatment failure (includes any 1 of the following criteria)

Death or readmission for heart failure through Day 7

Worsening symptoms and/or signs of heart failure

Persistent renal impairment (serum creatinine increases ≥0.3 mg/dL at Day 7, confirmed at Day 14).

Patient unchanged

Neither treatment success or treatment failure

Pilot Phase – Methods (1) 4 treatment arms evaluated in a double-blind fashion Placebo, rolofylline 10, 20, 30 mg Drug infused daily over 4 hours for 3 days Loop diuretic administered during study drug infusion Patients at intermediate risk for seizures were treated prophylactically with lorazepam (1 mg po) daily with the infusion of rolofylline

4 treatment arms evaluated in a double-blind fashion

Placebo, rolofylline 10, 20, 30 mg

Drug infused daily over 4 hours for 3 days

Loop diuretic administered during study drug infusion

Patients at intermediate risk for seizures were treated prophylactically with lorazepam (1 mg po) daily with the infusion of rolofylline

PROTECT Primary Endpoint 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Placebo (n=78) 10 mg (n=74) 20 mg (n=75) 30 mg (n=74) Treatment group % subjects Failure Unchanged Success

PROTECT 60 Day Outcomes: Death and Rehospitalization 1 30 mg vs placebo: HR 0.55 (95% CI = 0.28,1.04) Placebo Rolofylline (n=78) 10 mg (n=74) 20 mg (n=75) 30 mg (n=74) Death or cardiovascular or renal rehospitalization 1 33% 32% 24% 19% Death 10% 12% 8% 5% Rehospitalization for cardiovascular or renal causes 30% 22% 17% 16%

Conclusions The preservation of renal function with rolofylline is the first evidence that an intervention to prevent renal impairment may positively affect acute symptoms and 60-day outcome in patients with AHF. These pilot data have important implications not only for the development of this class but also for future therapeutic approaches to the treatment of acute decompensated HF. These preliminary results need to be confirmed by prospectively designed and appropriately powered multicenter Phase III pivotal trials that are currently under way.

The preservation of renal function with rolofylline is the first evidence that an intervention to prevent renal impairment may positively affect acute symptoms and 60-day outcome in patients with AHF.

These pilot data have important implications not only for the development of this class but also for future therapeutic approaches to the treatment of acute decompensated HF.

These preliminary results need to be confirmed by prospectively designed and appropriately powered multicenter Phase III pivotal trials that are currently under way.

Conclusions • Adenosin harmful in HF • A1 blockade promissing in Acute HF • Protect trial a deception • Drug w real benefit in acute heart failure still missing (and much needed)