MANAGEMENT OF THE SEVERELY MANAGEMENT OF THE SEVERELY SYMPTOMATIC PATIENTSYMPTOMATIC PATIENT

Overcoming Diuretic ResistanceOvercoming Diuretic Resistance

Dr TA McDonaghDr TA McDonaghConsultant CardiologistConsultant Cardiologist

Royal Brompton HospitalRoyal Brompton Hospital

Les Liaisons Dangereuses.?Les Liaisons Dangereuses.?

Diuretics and Mortality: SOLVDDiuretics and Mortality: SOLVD

6,797 in SOLVD Risk of hospitalization for, or death from, HF between

those taking a PSD and those who were not, adjusting for known covariates.

Domanski et al JACC 2003:42;705Domanski et al JACC 2003:42;705

Diuretics and the RAASDiuretics and the RAAS

12 HF patients12 HF patients Before and after Before and after

diureticsdiuretics

Bayliss J et al Br Heart J 1987;57:17Bayliss J et al Br Heart J 1987;57:17

DiureticsDiuretics

Which ?Which ?

As single agents-loop As single agents-loop diureticsdiuretics– Furosemide, Furosemide,

bumetanide, torasemidebumetanide, torasemide

Thiazides-usually Thiazides-usually adjunctiveadjunctive

Metolozone-thiazide likeMetolozone-thiazide like

Potassium sparingPotassium sparing– TriametereneTriameterene– AmilorideAmiloride– SprionolactoneSprionolactone

Diuretic ResistanceDiuretic Resistance

DefinitionDefinition– ““oedema despite adequate diuretic therapy”oedema despite adequate diuretic therapy”

Not well studiedNot well studied

– PrevalencePrevalence– Retrospective analysis of 1153 patients with Retrospective analysis of 1153 patients with

advanced CHF -34% had doses of advanced CHF -34% had doses of furosemide or equivalent>80mgfurosemide or equivalent>80mg

– Predicts mortalityPredicts mortality

Neuberg GW et al Neuberg GW et al Am Heart JAm Heart J 2002;144:31–8 2002;144:31–8

CausesCauses

Renal ImpairmentRenal Impairment

– CKD, common in CHFCKD, common in CHF– Most studied in CHF with LV Most studied in CHF with LV

Systolic DysfunctionSystolic Dysfunction– Despite exclusions 30-40% Despite exclusions 30-40%

had CKDhad CKD– Associated with worse Associated with worse

outcomesoutcomes

– CKD and AHF/DHFCKD and AHF/DHF– Prevalence-58% Prevalence-58%

(eGFR<60ml/min)(eGFR<60ml/min)– In hospital mortality 10%In hospital mortality 10%– Independent predictor of Independent predictor of

outcomeoutcome Maggioni et al Heart Failure Maggioni et al Heart Failure

20062006

RAAS activationRAAS activation Renovascular diseaseRenovascular disease Iatrogenic –NSAIDs, COX Iatrogenic –NSAIDs, COX

inhibitorsinhibitors

MechanismsMechanisms

– Delayed absorption of Delayed absorption of diuretic.diuretic.

– Reduced secretion of Reduced secretion of diuretic into the tubular diuretic into the tubular lumen (its site of action).lumen (its site of action).

– Compensatory retention of Compensatory retention of sodium after the effective sodium after the effective period of the diuretic.period of the diuretic.

Causes (2)Causes (2)

Chronic admin of loop diureticsChronic admin of loop diuretics

– diminished natriuretic effect -the "braking diminished natriuretic effect -the "braking phenomenon“phenomenon“

– hypertrophy and hyperplasia in epithelial cells hypertrophy and hyperplasia in epithelial cells of the distal convoluted tubule, leading to an of the distal convoluted tubule, leading to an increased reabsorption of sodium in this increased reabsorption of sodium in this segment (tubuloglomerular feedback)segment (tubuloglomerular feedback)

What to do ?What to do ?

ManagementManagementAdherence issuesAdherence issues

Na restriction<100mmols/dayNa restriction<100mmols/day

? NSAIDs? NSAIDs

– interfere with PG synthesis by inhibiting cyclo-interfere with PG synthesis by inhibiting cyclo-oxygenase and thereby antagonise the oxygenase and thereby antagonise the natriuretic response to loop diuretics natriuretic response to loop diuretics

ManagementManagementDose AdjustmentDose Adjustment

Increase doseIncrease dose More frequent administrationMore frequent administration

– loop diuretics are short acting, postdiuretic loop diuretics are short acting, postdiuretic salt retention is an important mechanism salt retention is an important mechanism contributing to diuretic resistance contributing to diuretic resistance

Try changing furosemide to bumetanide Try changing furosemide to bumetanide – >bioavailablility (80% vs 40%)>bioavailablility (80% vs 40%)

IV AdministrationIV Administration Overcomes bioavailability problemsOvercomes bioavailability problems

Continuous IV infusion may be more effectiveContinuous IV infusion may be more effective

– prevent postdiuretic salt retention completely prevent postdiuretic salt retention completely

– Some small studiesSome small studies

– Dose of furosemide ; 3 mg/hour - 200 mg/hour, Dose of furosemide ; 3 mg/hour - 200 mg/hour, (median 10–20 mg/hour; (median 10–20 mg/hour;

– Bumetanide was administered as 0.5 mg bolus Bumetanide was administered as 0.5 mg bolus followed by a continuous infusion of 0.5 mg /hour. followed by a continuous infusion of 0.5 mg /hour.

– Same daily dose caused excretion of a > volume Same daily dose caused excretion of a > volume of urine and electrolytes when given as a of urine and electrolytes when given as a continuous infusion. continuous infusion.

– The maximal plasma furosemide concentration The maximal plasma furosemide concentration was significantly lower and this resulted in a was significantly lower and this resulted in a reduced risk for ototoxic side effects reduced risk for ototoxic side effects

Dormans TPJ et al JACC 1996;28:376–82 . Dormans TPJ et al JACC 1996;28:376–82 . Ferguson JA et al; Clin Pharmacol Ther Ferguson JA et al; Clin Pharmacol Ther 1997;62:203–8.1997;62:203–8.

Combining DiureticsCombining DiureticsSequential Nephron BlockadeSequential Nephron Blockade

3 studies with addition of thiazides3 studies with addition of thiazides

– significant weight loss significant weight loss – improvement in NYHA class improvement in NYHA class – side effects ;hypokalaemia, hyponatraemia, side effects ;hypokalaemia, hyponatraemia,

dehydration, and renal failure dehydration, and renal failure – no advantage to metolozoneno advantage to metolozone

Kiyingi A,et al. Lancet 1990;335:29–31Kiyingi A,et al. Lancet 1990;335:29–31

Channer KS, et al. Br Heart J 1994;71:146–50.Channer KS, et al. Br Heart J 1994;71:146–50.

Dormans TPJ et al, Eur Heart J 1996;17:1867–Dormans TPJ et al, Eur Heart J 1996;17:1867–7474

Other optionsOther options

In decompensated HF or cardiogenic shockIn decompensated HF or cardiogenic shock

If SBP low, add an inotrope on the short termIf SBP low, add an inotrope on the short term

““Renal dose dopamine”Renal dose dopamine”– Low doses (<2 µg/kg/min iv) Low doses (<2 µg/kg/min iv)

– peripheral dopaminergic (DA1) receptorsperipheral dopaminergic (DA1) receptors– ↓↓peripheral VRperipheral VR– vasodilation : renal, splanchnic, coronary, and vasodilation : renal, splanchnic, coronary, and

cerebral vascular beds cerebral vascular beds – ↑↑ renal blood flow, GFR, diuresis, and Na excretion, renal blood flow, GFR, diuresis, and Na excretion, – ↑↑ response to diuretic agents, in renal response to diuretic agents, in renal

hypoperfusion and failure hypoperfusion and failure – Class of recommendation IIb, level of evidence CClass of recommendation IIb, level of evidence C

ACEI/ARB and Worsening Renal ACEI/ARB and Worsening Renal FunctionFunction

Some in Some in urea/creatinine/ K urea/creatinine/ K+ +

expected. Small expected. Small and and asymptomatic-no actionasymptomatic-no action

in creatinine up to 50% above in creatinine up to 50% above baseline or to 266µmol/lbaseline or to 266µmol/l

KK++ ≤5.5mmol/l ≤5.5mmol/l

Caution-seek specialist advice if Caution-seek specialist advice if baseline Kbaseline K++≥5.0mmol/l or > ≥5.0mmol/l or > 221µmol/l221µmol/l

Monitor more frequently in CKDMonitor more frequently in CKD

Excessive rise: stop nephrotoxic Excessive rise: stop nephrotoxic drugs-NSAIDs, non-essential drugs-NSAIDs, non-essential vasodilators, Kvasodilators, K++ supplements/sparingsupplements/sparing

diuretics, recheck, diuretics, recheck, reduce diuretic reduce diuretic

Persists-half ACEI and recheckPersists-half ACEI and recheck

KK++≥5.5mmol/l or if creatinine ≥5.5mmol/l or if creatinine 100% or to >310µmol/l,100% or to >310µmol/l, stop ACEI/ARBstop ACEI/ARB

Monitor U&Es closely untilMonitor U&Es closely untilcreatinine and Kcreatinine and K++ stable stable

McMurray et al Eur J Heart Fail 2005 McMurray et al Eur J Heart Fail 2005 7:7107:710

Novel Approaches…Novel Approaches…

DR I

M

KRG

S SS

SGLG

FC

CS S

GSGQVM

K V L RR

H

KPS

NesiritidePrimary Amino Acid Sequence of (hBNP)

Clemens LE, Protter AA, et al. J Pharmacol Exp Ther 1998;287:67-71

Effect of Short-Term Nesiritide Effect of Short-Term Nesiritide vs vs

Dobutamine on 6-Month Dobutamine on 6-Month SurvivalSurvival

Silver MA et al. J Am Coll Cardiol. 2002;39:798–803.

Cum

ulat

ive

Mor

talit

y R

ate

(%)

Treatment Duration (d)

Log-rank test:Dobutamine vs nesiritide, 0.015 g/kg/min: P = 0.040Dobutamine vs nesiritide, 0.030 g/kg/min: P = 0.366

Dobutamine (n = 58)

Nesiritide, 0.030 g/kg/min(n = 103)

Nesiritide, 0.015 g/kg/min(n = 100)

0

5

10

15

20

25

30

35

0 30 60 90 120 150 180

But….But….

Reference: Sackner-Bernstein JD et al. Circulation 2005;111:1487-1491

Rate of SCr Increase >0.5 mg/dL at Rate of SCr Increase >0.5 mg/dL at Any Time: Nesiritide vs ControlAny Time: Nesiritide vs Control

ControlControlN (%)N (%)

nesiritidenesiritideN (%)N (%)

Mills et al. (311)Mills et al. (311) 4/29 (14%)4/29 (14%) 15/74 (20%)15/74 (20%)

Efficacy (325)Efficacy (325) 2/42 (5%)2/42 (5%) 15/85 (18%)15/85 (18%)

Comparative (326)Comparative (326) 9/102 (9%)9/102 (9%) 36/203 (18%)36/203 (18%)

PRECEDENT (329)PRECEDENT (329) 9/83 (11%)9/83 (11%) 29/162 (18%)29/162 (18%)

VMAC (339)VMAC (339) 45/216 (21%)45/216 (21%) 74/273 (27%)74/273 (27%)

All 5 studies pooledAll 5 studies pooled11 69/473 (15%)69/473 (15%) 169/797 (21%)169/797 (21%)

References: 1. Sackner-Bernstein JD et al. Circulation 2005;111:1487-14912. Data on File, Scios Inc.

And…And…

Reference: Sackner-Bernstein JD et al. JAMA. 2005;293(15):1900-1905.

Sackner-Bernstein JD et al. JAMA 2005; 293:1900-1905.

30-day mean survival by treatment 30-day mean survival by treatment and nesiritide mortality HR in meta-and nesiritide mortality HR in meta-

analysisanalysis

Calculation Calculation Nesiritide Nesiritide (%) (%)

Control Control (%) (%)

HR HR (95% CI) (95% CI)

p p

Unadjusted Unadjusted 93.593.5 96.096.0 1.861.86(1.02-3.41)(1.02-3.41)

0.040.04

Adjusted Adjusted —— —— 1.801.80(0.98-3.31)(0.98-3.31)

0.0570.057

The future ?The future ?

RAPID HFRAPID HFAcute Decompensated Heart FailureAcute Decompensated Heart Failure

Peripheral veno-venous ultrafiltrationPeripheral veno-venous ultrafiltration 40 hospitalised patients40 hospitalised patients

– Fluid retentionFluid retention 20 randomised to 8 hours of ultrafiltration 20 randomised to 8 hours of ultrafiltration

plus usual careplus usual care– Improved symptomsImproved symptoms

End pointEnd point UltrafiltratioUltrafiltration (n=20)n (n=20)

Usual care Usual care (n=20)(n=20)

pp

Weight loss 24 h Weight loss 24 h (kg) (kg)

2.5 2.5 1.861.86 0.2400.240

Fluid removal 24 Fluid removal 24 h (mL)h (mL)

46504650 28382838 0.0010.001

Bart BA et al. J Am Coll Cardiol 2005; 46:2043-2046.

UNLOADUNLOAD

200 patients, ADHF200 patients, ADHF Randomised to Randomised to

ultrafiltration/iv ultrafiltration/iv diureticdiuretic

UltrafiltrationUltrafiltration– significantly > fluid significantly > fluid

loss over 48 hours loss over 48 hours (p=0.001) (p=0.001)

– Similar effects of Similar effects of creatininecreatinine

Costanzo M et al. JACC 2007; 49;675

Adenosine A1 Receptor AntagonistAdenosine A1 Receptor AntagonistIV KW-3902 (Rolofylline) in ADHF (146) with IV KW-3902 (Rolofylline) in ADHF (146) with

renal dysfunctionrenal dysfunction

ParameterParameter 2.5 mg, 2.5 mg, n=29n=29

15 mg, 15 mg, n=31n=31

30 mg, 30 mg, n=30n=30

60 mg, 60 mg, n=29n=29

Placebo, Placebo, n=27n=27

6-hour urine output on 6-hour urine output on day 1 (mL)day 1 (mL)

445445 531531 631*631* 570570 374374

Creatinine, baseline Creatinine, baseline (mg/dL)(mg/dL)

1.631.63 1.811.81 1.691.69 1.771.77 1.861.86

Creatinine, change from Creatinine, change from baseline (mg/dL)baseline (mg/dL)

-0.07-0.07 -0.04-0.04 -0.09-0.09 +0.03+0.03 -0.01-0.01

Total furosemide dose Total furosemide dose (mg)(mg)

397397 331*331* 342342 229*229* 606606

Early withdrawal of Early withdrawal of therapy due to adequate therapy due to adequate diuresis (%)diuresis (%)

1414 3939 3030 3838 44

*p<0.05 vs placebo

Givertz MM, JACC 2007;50;1551

AVP-VAVP-V22 Antagonist TOLVAPTAN Antagonist TOLVAPTAN“EVEREST”“EVEREST”

RCT, n=4133, LVEF<40%RCT, n=4133, LVEF<40% Admitted with HF-persistent “congestion” after Admitted with HF-persistent “congestion” after

standard Rxstandard Rx Tolvaptan, 30mg/placeboTolvaptan, 30mg/placebo Primary: all-cause mortality (superiority and Primary: all-cause mortality (superiority and

noninferiority) and CV death or hospitalization noninferiority) and CV death or hospitalization for HF (superiority only). for HF (superiority only).

Secondary : changes in dyspnoea, body weight, Secondary : changes in dyspnoea, body weight, and oedema and oedema

Konstam, M. A. et al. JAMA 2007;297:1319-1331.

Konstam, M. A. et al. JAMA 2007;297:1319-1331

““EVEREST”EVEREST”

Konstam, M. A. et al. JAMA 2007;297:1319-1331

““EVEREST”EVEREST”

““EVEREST”EVEREST”

Konstam, M. A. et al. JAMA 2007;297:1319-1331

Diuretic Resistance in Heart FailureDiuretic Resistance in Heart Failure

Common problemCommon problem Difficult to manageDifficult to manage

– Standard measures inadequateStandard measures inadequate

Newer therapies promisingNewer therapies promising– ΑΑ1-adenosine receptor antagonists1-adenosine receptor antagonists– UltrafiltrationUltrafiltration– AVP antagonistsAVP antagonists

Diuretic Resistance and HFDiuretic Resistance and HF