A Prospective Randomized Trial of A Prospective Randomized Trial of

Furosemide-Induced High-Volume Diuresis Furosemide-Induced High-Volume Diuresis

with Matched Hydration Using a Dedicated with Matched Hydration Using a Dedicated

Device to Prevent Contrast NephropathyDevice to Prevent Contrast Nephropathy

The MYTHOS TrialThe MYTHOS Trial

Antonio L. Bartorelli, MDAntonio L. Bartorelli, MDCentro Cardiologico MonzinoCentro Cardiologico Monzino

Department of Cardiovascular SciencesDepartment of Cardiovascular Sciences

University of MilanUniversity of Milan

ItalyItaly

Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest

• Consulting fees/HonorariaConsulting fees/Honoraria

• Speaker’s bureauSpeaker’s bureau

• Speaker’s bureauSpeaker’s bureau

• Abbott VascularAbbott Vascular

• Johnson & Johnson CordisJohnson & Johnson Cordis

• BraccoBracco

Within the past 12 months, I or my spouse/partner have had a financial Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Background (I)Background (I)

• Contrast-induced nephropathy (CIN) is a frequent complication Contrast-induced nephropathy (CIN) is a frequent complication of diagnostic and interventional procedures, associated with of diagnostic and interventional procedures, associated with in-hospital and long-term unfavorable outcomesin-hospital and long-term unfavorable outcomes

• Intravenous hydration with isotonic saline solution has been Intravenous hydration with isotonic saline solution has been shown to protect against CINshown to protect against CIN

• However, hydration is usually performed at a rate significantly However, hydration is usually performed at a rate significantly lower than that shown to provide protection for logistic reasons lower than that shown to provide protection for logistic reasons and fear of over-hydration and pulmonary edema, particularly and fear of over-hydration and pulmonary edema, particularly in patients with reduced LV functionin patients with reduced LV function

Background (II)Background (II)• Diuretics have been used to prevent over-hydration and to protect the kidney Diuretics have been used to prevent over-hydration and to protect the kidney

against CIN by:against CIN by: Increasing urine flowIncreasing urine flow that results in greater contrast dilution within the renal tubules that results in greater contrast dilution within the renal tubules

and lower direct kidney toxicityand lower direct kidney toxicity Reducing medullary ischemiaReducing medullary ischemia due to decreased tubular sodium re-absorption and, due to decreased tubular sodium re-absorption and,

consequently, oxygen consumptionconsequently, oxygen consumption

• However, by decreasing intravascular volume diuretics may induce However, by decreasing intravascular volume diuretics may induce vasoconstriction (vasoconstriction (a mechanism involved in CIN pathogenesisa mechanism involved in CIN pathogenesis) and may ) and may exacerbate that produced by contrast agent itself, thus increasing CIN risk exacerbate that produced by contrast agent itself, thus increasing CIN risk ((Solomon et al. NEJM 1993Solomon et al. NEJM 1993))

• If we were able to maintain the positive effects of diuretics and at the same 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 time counteract their adverse effects, we could possibly shift our balance toward an overall benefit in terms of CIN preventiontoward an overall benefit in terms of CIN prevention

Study PurposeStudy Purpose

• The aim of the MYTHOS trial was to evaluate if furosemide-induced The aim of the MYTHOS trial was to evaluate if furosemide-induced high-volume diuresis with concurrent maintenance of intravascular high-volume diuresis with concurrent maintenance of intravascular volume may prevent CIN in high-risk patientsvolume may prevent CIN in high-risk patients

• To this purpose, we investigated the effect of a new CIN preventive To this purpose, we investigated the effect of a new CIN preventive strategy based on a dedicated device (RenalGuard System), which is strategy based on a dedicated device (RenalGuard System), which is able of delivering i.v. saline solution in an amount automatically matched 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 to the volume of urine produced in response to an i.v. bolus of furosemide furosemide

RenalGuard TherapyRenalGuard Therapy

• RenalGuard therapy is designed to:RenalGuard therapy is designed to: Automatically match i.v. fluid replacement to urine volume in real-Automatically match i.v. fluid replacement to urine volume in real-

time during furosemide-induced forced diuresistime 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 agent Limit kidneys exposure to contrast agent

RenalGuard SystemRenalGuard System

Study ProtocolStudy Protocol

157 ptsElectiveElective

ProceduresProceduresn= 94n= 94

Urgent (<24 hrs)Urgent (<24 hrs)proceduresprocedures(NSTEMI)(NSTEMI)

n= 63n= 63

RenalGuardRenalGuardn=80n=80

Standard i.v. hydration Standard i.v. hydration (1 ml/kg/hr)(1 ml/kg/hr)

for 12 hrs before and for 12 hrs before and after procedureafter procedure

n=77n=77

Primary end point: CIN (Primary end point: CIN (>>0.5 mg/dl or 0.5 mg/dl or >>25% sCr increase during first 72 hrs)25% sCr increase during first 72 hrs)Secondary end points: In-hospital MACE (acute pulmonary edema, Secondary end points: In-hospital MACE (acute pulmonary edema,

cardiogenic shock, MI, need for RRT, severe arrhythmias, and death)cardiogenic shock, MI, need for RRT, severe arrhythmias, and death)

Consecutive CKD patients Consecutive CKD patients (eGFR<60ml/min/1.73m2) undergoing coronary ) undergoing coronary angiography between September 1, 2008 and September 15, 2010 angiography between September 1, 2008 and September 15, 2010

Study ProtocolStudy Protocol

• Exclusion criteria:Exclusion criteria: Primary/rescue PCIPrimary/rescue PCI Cardiogenic shockCardiogenic shock Overt CHFOvert CHF Acute respiratory failureAcute respiratory failure Chronic dialysisChronic dialysis Known to be unsuitable for Foley catheter placement Known to be unsuitable for Foley catheter placement

• Renoprotective drugs were not administeredRenoprotective drugs were not administered

• A non-ionic, low-osmolar contrast agent (Iomeron) was A non-ionic, low-osmolar contrast agent (Iomeron) was used in all patientsused in all patients

>300 ml/hr of UO 4 hours

250 mli.v. saline

i.v. furosemide*(0.5 mg/kg)

RenalGuard

30 min.

PRE-PROCEDURE PROCEDURE POST-PROCEDURE

Continuous Infusion of Matched Replacement SalineNurse 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* In 20% of pts additional furosemide (0.5 mg/Kg) was required

Study ProtocolStudy Protocol

Baseline Clinical and Baseline Clinical and Procedural CharacteristicsProcedural Characteristics

RenalGuardRenalGuard Control Control P value P value Group Group (n=80)(n=80) Group Group (n=77)(n=77)

Age (yrs)Age (yrs) 727277 747488 NS NS Men Men 64 (80%)64 (80%) 61 (70%)61 (70%) NSNSWeight (kg)Weight (kg) 76761414 73731212 NS NS SmokersSmokers 28 (35%)28 (35%) 32 (42%)32 (42%) NSNSDiabetes mellitusDiabetes mellitus 33 (41%)33 (41%) 25 (32%)25 (32%) NSNSHypertensionHypertension 64 (80%)64 (80%) 64 (83%)64 (83%) NSNSDyslipidemiaDyslipidemia 56 (70%)56 (70%) 43 (69%)43 (69%) NSNSPrior MI Prior MI 39 (49%)39 (49%) 31 (40%)31 (40%) NSNSPrior CABG Prior CABG 24 (30%)24 (30%) 18 (23%)18 (23%) NSNSPrior PCIPrior PCI 44 (55%)44 (55%) 30 (39%)30 (39%) NS NS Elective PCIElective PCI 45 (56%)45 (56%) 49 (64%)49 (64%) NSNSUrgent PCIUrgent PCI 35 (44%)35 (44%) 28 (36%)28 (36%) NSNSMean LVEF (%)Mean LVEF (%) 52521212 52521313 NSNSSerum creatinine (mg/dl)Serum creatinine (mg/dl) 1.81.80.60.6 1.71.70.50.5 NSNSeGFR (ml/min/1.73 meGFR (ml/min/1.73 m22)) 38381111 41411010 NSNSSodium (mEq/l)Sodium (mEq/l) 14014022 13913933 NSNSPotassium (mEq/l)Potassium (mEq/l) 4.14.10.80.8 4.44.40.60.6 NSNSHemoglobin (g/dl)Hemoglobin (g/dl) 12.212.21.81.8 12.312.31.81.8 NSNSCoronary angiography Coronary angiography 80 (100%)80 (100%) 77 (100%)77 (100%) NSNSPCIPCI 44 (55%)44 (55%) 48 (62%) 48 (62%) NSNSContrast volume (ml)Contrast volume (ml) 188188106106 206206112112 NSNSACE-inhibitors ACE-inhibitors 50 (62%)50 (62%) 54 (70%)54 (70%) NSNSAspirin Aspirin 70 (88%)70 (88%) 71 (92%)71 (92%) NSNSDiuretics Diuretics 44 (55%)44 (55%) 43 (56%)43 (56%) NSNSPeri-PCI bleedingPeri-PCI bleeding 3 (4%) 3 (4%) 2 (3%) 2 (3%) NSNS

RenalGuard Control P RenalGuard Control P valuevalue

GroupGroup GroupGroup (n=80)(n=80) (n=77)(n=77)

Diabetes mellitusDiabetes mellitus 33 (41%)33 (41%) 25 (32%)25 (32%) NSNS

Serum creatinine (mg/dl)Serum creatinine (mg/dl) 1.81.80.60.6 1.71.70.50.5 NSNS

eGFR (ml/min/1.73 meGFR (ml/min/1.73 m22)) 38381111 41411010 NSNS

Contrast volume (ml)Contrast volume (ml)188188106106 216216112112 NSNS

0

5

10

15

20

25

30

Incidence of CINIncidence of CIN

%

All patients NSTEMI Elective procedures

16%

Controls

RenalGuard

5% 6%

10%

25%P=0.028

4%

P=0.03

P NS-69%-69%-80%-80%

-60%-60%

In-Hospital Complications In-Hospital Complications

RenalGuardRenalGuard Control P valueControl P value GGrouproup GroupGroup

(n=80) (n=80) (n=77) (n=77)

CIN requiring RRT CIN requiring RRT 1 (1.2%)1 (1.2%)3 (4%)3 (4%) NS NS

Acute myocardial infarctionAcute myocardial infarction 0 (0%)0 (0%) 1 (1.3%)1 (1.3%) NS NS

Atrial fibrillationAtrial fibrillation 0 (0%)0 (0%) 2 (3%)2 (3%) NS NS

Emergency CABGEmergency CABG 0 (0%)0 (0%) 0 (0%)0 (0%) NS NS

Acute heart failureAcute heart failure 5 (6%)5 (6%) 9 (12%)9 (12%) NS NS

Hypotension/shock Hypotension/shock 0 (0%)0 (0%) 0 (0%)0 (0%) NS NS

In-hospital deathIn-hospital death 1 (1.2%)1 (1.2%)3 (4%)3 (4%) NS NS

All clinical eventsAll clinical events 7 (9%)7 (9%) 18 (23%) 0.01218 (23%) 0.012

RRT= renal replacement therapy

0

10

20

30

40

50

Composite End PointComposite End Point (CIN and MACE)(CIN and MACE)

% RenalGuard

Control39 %

14 %

p <0.001

-64%-64%

ConclusionsConclusions

• Maintenance of intravascular volume after furosemide-Maintenance of intravascular volume after furosemide-induced forced diuresis can be safely and effectively obtained induced forced diuresis can be safely and effectively obtained with the RenalGuard Systemwith the RenalGuard System

• This preventive strategy significantly reduced the incidence of This preventive strategy significantly reduced the incidence of CIN and in-hospital MACE in CKD patients undergoing PCI CIN and in-hospital MACE in CKD patients undergoing PCI

• The positive results were mainly driven by the effect obtained The positive results were mainly driven by the effect obtained with this treatment in NSTEMI patients undergoing urgent with this treatment in NSTEMI patients undergoing urgent (<24 hrs) PCI(<24 hrs) PCI

A New Concept is Emerging A New Concept is Emerging for CIN Prevention for CIN Prevention

• The hydration volume should be commensurate to the patient’s The hydration volume should be commensurate to the patient’s riskrisk

• A high volume (~1 L/hr) of controlled hydration is likely required in A high volume (~1 L/hr) of controlled hydration is likely required in high-risk patientshigh-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 Exactly matching fluid removal to high-volume i.v. hydration to

prevent fluid overload (prevent fluid overload (HemofiltrationHemofiltration) ) Exactly matching i.v. hydration to furosemide-induced high-Exactly matching i.v. hydration to furosemide-induced high-

volume diuresis to avoid hypovolemia (volume diuresis to avoid hypovolemia (RenalGuardRenalGuard) )