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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
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Les Liaisons Dangereuses.?Les Liaisons Dangereuses.?
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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
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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
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DiureticsDiuretics
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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
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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
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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.
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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)
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What to do ?What to do ?
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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
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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%)
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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.
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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
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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
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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
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Novel Approaches…Novel Approaches…
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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
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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
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But….But….
Reference: Sackner-Bernstein JD et al. Circulation 2005;111:1487-1491
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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.
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And…And…
Reference: Sackner-Bernstein JD et al. JAMA. 2005;293(15):1900-1905.
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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
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The future ?The future ?
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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.
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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
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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
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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.
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Konstam, M. A. et al. JAMA 2007;297:1319-1331
““EVEREST”EVEREST”
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Konstam, M. A. et al. JAMA 2007;297:1319-1331
““EVEREST”EVEREST”
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““EVEREST”EVEREST”
Konstam, M. A. et al. JAMA 2007;297:1319-1331
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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
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Diuretic Resistance and HFDiuretic Resistance and HF
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