A Prospective Randomized Trial of Furosemide-Induced High-Volume Diuresis with Matched Hydration Using a Dedicated Device to Prevent Contrast Nephropathy The MYTHOS Trial Antonio L. Bartorelli, MD Centro Cardiologico Monzino Department of Cardiovascular Sciences University of Milan University of Milan Italy Italy

Disclosure Statement of Financial Interest Consulting fees/Honoraria Consulting fees/Honoraria Speaker’s bureau Speaker’s bureau Abbott Vascular Abbott Vascular Johnson & Johnson Cordis Johnson & Johnson Cordis Bracco Bracco Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany

Background (I) Contrast-induced nephropathy (CIN) is a frequent complication of diagnostic and interventional procedures, associated with in-hospital and long-term unfavorable outcomes Contrast-induced nephropathy (CIN) is a frequent complication of diagnostic and interventional procedures, associated with in-hospital and long-term unfavorable outcomes Intravenous hydration with isotonic saline solution has been shown to protect against CIN Intravenous hydration with isotonic saline solution has been shown to protect against CIN However, hydration is usually performed at a rate significantly lower than that shown to provide protection for logistic reasons and fear of over-hydration and pulmonary edema, particularly in patients with reduced LV function However, hydration is usually performed at a rate significantly lower than that shown to provide protection for logistic reasons and fear of over-hydration and pulmonary edema, particularly in patients with reduced LV function

Background (II) Diuretics have been used to prevent over-hydration and to protect the kidney against CIN by: Diuretics have been used to prevent over-hydration and to protect the kidney against CIN by:  Increasing urine flow that results in greater contrast dilution within the renal tubules and lower direct kidney toxicity  Reducing medullary ischemia due to decreased tubular sodium re-absorption and, consequently, oxygen consumption However, by decreasing intravascular volume diuretics may induce vasoconstriction (a mechanism involved in CIN pathogenesis) and may exacerbate that produced by contrast agent itself, thus increasing CIN risk (Solomon et al. NEJM 1993) However, by decreasing intravascular volume diuretics may induce vasoconstriction (a mechanism involved in CIN pathogenesis) and may exacerbate that produced by contrast agent itself, thus increasing CIN risk (Solomon et al. NEJM 1993) If we were able to maintain the positive effects of diuretics and at the same time counteract their adverse effects, we could possibly shift our balance toward an overall benefit in terms of CIN prevention If we were able to maintain the positive effects of diuretics and at the same time counteract their adverse effects, we could possibly shift our balance toward an overall benefit in terms of CIN prevention

Study Purpose The aim of the MYTHOS trial was to evaluate if furosemide- induced high-volume diuresis with concurrent maintenance of intravascular volume may prevent CIN in high-risk patients The aim of the MYTHOS trial was to evaluate if furosemide- induced high-volume diuresis with concurrent maintenance of intravascular volume may prevent CIN in high-risk patients To this purpose, we investigated the effect of a new CIN preventive strategy based on a dedicated device (RenalGuard System), which is able of delivering i.v. saline solution in an amount automatically matched to the volume of urine produced in response to an i.v. bolus of furosemide To this purpose, we investigated the effect of a new CIN preventive strategy based on a dedicated device (RenalGuard System), which is able of delivering i.v. saline solution in an amount automatically matched to the volume of urine produced in response to an i.v. bolus of furosemide

RenalGuard Therapy RenalGuard therapy is designed to:RenalGuard therapy is designed to:  Automatically match i.v. fluid replacement to urine volume in real-time during furosemide-induced forced diuresis This treatment may:This treatment may: Reduce the risk of over- or under- hydrationReduce the risk of over- or under- hydration Dilute contrast agent in the renal tubulesDilute contrast agent in the renal tubules Limit kidneys exposure to contrast agentLimit kidneys exposure to contrast agent

RenalGuard System

Study Protocol 157 pts ElectiveProcedures n= 94 Urgent (<24 hrs) procedures(NSTEMI) n= 63 RenalGuardn=80 Standard i.v. hydration Standard i.v. hydration (1 ml/kg/hr) for 12 hrs before and after procedure n=77 Primary end point: CIN (>0.5 mg/dl or >25% sCr increase during first 72 hrs) Secondary end points: In-hospital MACE (acute pulmonary edema, cardiogenic shock, MI, need for RRT, severe arrhythmias, and death) Consecutive CKD patients ) undergoing coronary angiography between September 1, 2008 and September 15, 2010 Consecutive CKD patients (eGFR<60ml/min/1.73m 2 ) undergoing coronary angiography between September 1, 2008 and September 15, 2010

Study Protocol Exclusion criteria: Exclusion criteria:  Primary/rescue PCI  Cardiogenic shock  Overt CHF  Acute respiratory failure  Chronic dialysis  Known to be unsuitable for Foley catheter placement Renoprotective drugs were not administered Renoprotective drugs were not administered A non-ionic, low-osmolar contrast agent (Iomeron) was used in all patients A non-ionic, low-osmolar contrast agent (Iomeron) was used in all patients

>300 ml/hr of UO 4 hours 250 ml i.v. saline i.v. furosemide* (0.5 mg/kg) RenalGuard 30 min. PRE-PROCEDUREPROCEDUREPOST-PROCEDURE Continuous Infusion of Matched Replacement Saline Nurse monitors patient and record data every 30 min. mean urine output 826±342 ml/hr 48±16 min * In 20% of pts additional furosemide (0.5 mg/Kg) was required Study Protocol

Baseline Clinical and Procedural Characteristics Baseline Clinical and Procedural Characteristics RenalGuard Control P value RenalGuard Control P value Group (n=80) Group (n=77) Group (n=80) Group (n=77) Age (yrs)72  774  8NS Age (yrs)72  774  8NS Men 64 (80%)61 (70%)NS Weight (kg)76  1473  12NS Smokers28 (35%)32 (42%)NS Diabetes mellitus33 (41%)25 (32%)NS Hypertension64 (80%)64 (83%)NS Dyslipidemia 56 (70%)43 (69%)NS Prior MI 39 (49%)31 (40%)NS Prior CABG 24 (30%)18 (23%)NS Prior PCI44 (55%)30 (39%)NS Elective PCI45 (56%)49 (64%)NS Urgent PCI35 (44%)28 (36%)NS Mean LVEF (%)52  1252  13NS Serum creatinine (mg/dl)1.8   0.5NS eGFR (ml/min/1.73 m 2 )38  1141  10NS Sodium (mEq/l)140  2139  3NS Potassium (mEq/l)4.1   0.6NS Hemoglobin (g/dl)12.2   1.8NS Coronary angiography 80 (100%)77 (100%)NS PCI 44 (55%)48 (62%) NS Contrast volume (ml)188   112NS ACE-inhibitors 50 (62%)54 (70%)NS Aspirin 70 (88%)71 (92%)NS Diuretics 44 (55%)43 (56%)NS Peri-PCI bleeding 3 (4%) 2 (3%)NS RenalGuard Control P value RenalGuard Control P value Group Group Group Group (n=80) (n=77) (n=80) (n=77) Diabetes mellitus33 (41%)25 (32%)NS Serum creatinine (mg/dl)1.8   0.5NS eGFR (ml/min/1.73 m 2 )38  1141  10NS Contrast volume (ml)188   112NS

Incidence of CIN Incidence of CIN % All patients NSTEMI Elective procedures 16% Controls RenalGuard 5% 6% 10% 25% P= % P=0.03 P NS -69% -80% -60%

In-Hospital Complications RenalGuardControl P value RenalGuardControl P value G roup Group G roup Group (n=80) (n=77) (n=80) (n=77) CIN requiring RRT 1 (1.2%)3 (4%) NS Acute myocardial infarction0 (0%)1 (1.3%) NS Atrial fibrillation0 (0%)2 (3%) NS Emergency CABG0 (0%)0 (0%) NS Acute heart failure5 (6%)9 (12%) NS Hypotension/shock 0 (0%)0 (0%) NS In-hospital death1 (1.2%)3 (4%) NS All clinical events7 (9%)18 (23%) RRT= renal replacement therapy

Composite End Point (CIN and MACE) % RenalGuard Control 39 % 14 % p < %

Conclusions Maintenance of intravascular volume after furosemide- induced forced diuresis can be safely and effectively obtained with the RenalGuard System Maintenance of intravascular volume after furosemide- induced forced diuresis can be safely and effectively obtained with the RenalGuard System This preventive strategy significantly reduced the incidence of CIN and in-hospital MACE in CKD patients undergoing PCI This preventive strategy significantly reduced the incidence of CIN and in-hospital MACE in CKD patients undergoing PCI The positive results were mainly driven by the effect obtained with this treatment in NSTEMI patients undergoing urgent (<24 hrs) PCI The positive results were mainly driven by the effect obtained with this treatment in NSTEMI patients undergoing urgent (<24 hrs) PCI

A New Concept is Emerging for CIN Prevention The hydration volume should be commensurate to the patient’s risk The hydration volume should be commensurate to the patient’s risk A high volume (~1 L/hr) of controlled hydration is likely required in high-risk patients A high volume (~1 L/hr) of controlled hydration is likely required in high-risk patients This goal can be achieved by: This goal can be achieved by:  Exactly matching fluid removal to high-volume i.v. hydration to prevent fluid overload (Hemofiltration)  Exactly matching i.v. hydration to furosemide-induced high- volume diuresis to avoid hypovolemia (RenalGuard)