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MANAGEMENT OF THE SEVERELY SYMPTOMATIC PATIENT Overcoming Diuretic Resistance

MANAGEMENT OF THE SEVERELY SYMPTOMATIC PATIENT Overcoming Diuretic Resistance. Dr TA McDonagh Consultant Cardiologist Royal Brompton Hospital. Les Liaisons Dangereuses.?. Diuretics and Mortality: SOLVD. 6,797 in SOLVD

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MANAGEMENT OF THE SEVERELY SYMPTOMATIC PATIENT Overcoming Diuretic Resistance

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  1. MANAGEMENT OF THE SEVERELY SYMPTOMATIC PATIENTOvercoming Diuretic Resistance Dr TA McDonagh Consultant Cardiologist Royal Brompton Hospital

  2. Les Liaisons Dangereuses.?

  3. Diuretics 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;705

  4. 12 HF patients Before and after diuretics Diuretics and the RAAS Bayliss J et al Br Heart J 1987;57:17

  5. Diuretics

  6. Which ? • As single agents-loop diuretics • Furosemide, bumetanide, torasemide • Thiazides-usually adjunctive • Metolozone-thiazide like • Potassium sparing • Triameterene • Amiloride • Sprionolactone

  7. Diuretic Resistance • Definition • “oedema despite adequate diuretic therapy” • Not well studied • Prevalence • Retrospective analysis of 1153 patients with advanced CHF -34% had doses of furosemide or equivalent>80mg • Predicts mortality Neuberg GW et al Am Heart J 2002;144:31–8

  8. Renal Impairment CKD, common in CHF Most studied in CHF with LV Systolic Dysfunction Despite exclusions 30-40% had CKD Associated with worse outcomes CKD and AHF/DHF Prevalence-58% (eGFR<60ml/min) In hospital mortality 10% Independent predictor of outcome Maggioni et al Heart Failure 2006 RAAS activation Renovascular disease Iatrogenic –NSAIDs, COX inhibitors Mechanisms Delayed absorption of diuretic. Reduced secretion of diuretic into the tubular lumen (its site of action). Compensatory retention of sodium after the effective period of the diuretic. Causes

  9. Causes (2) • Chronic admin of loop diuretics • diminished natriuretic effect -the "braking phenomenon“ • hypertrophy and hyperplasia in epithelial cells of the distal convoluted tubule, leading to an increased reabsorption of sodium in this segment (tubuloglomerular feedback)

  10. What to do ?

  11. ManagementAdherence issues • Na restriction<100mmols/day • ? NSAIDs • interfere with PG synthesis by inhibiting cyclo-oxygenase and thereby antagonise the natriuretic response to loop diuretics

  12. ManagementDose Adjustment • Increase dose • More frequent administration • loop diuretics are short acting, postdiuretic salt retention is an important mechanism contributing to diuretic resistance • Try changing furosemide to bumetanide • >bioavailablility (80% vs 40%)

  13. IV Administration • Overcomes bioavailability problems • Continuous IV infusion may be more effective • prevent postdiuretic salt retention completely • Some small studies • Dose of furosemide ; 3 mg/hour - 200 mg/hour, (median 10–20 mg/hour; • Bumetanide was administered as 0.5 mg bolus followed by a continuous infusion of 0.5 mg /hour. • Same daily dose caused excretion of a > volume of urine and electrolytes when given as a continuous infusion. • The maximal plasma furosemide concentration was significantly lower and this resulted in a reduced risk for ototoxic side effects Dormans TPJ et al JACC 1996;28:376–82 . Ferguson JA et al; Clin Pharmacol Ther 1997;62:203–8.

  14. Combining DiureticsSequential Nephron Blockade • 3 studies with addition of thiazides • significant weight loss • improvement in NYHA class • side effects ;hypokalaemia, hyponatraemia, dehydration, and renal failure • no advantage to metolozone Kiyingi A,et al. Lancet 1990;335:29–31 Channer KS, et al. Br Heart J 1994;71:146–50. Dormans TPJ et al, Eur Heart J 1996;17:1867–74

  15. Other options • In decompensated HF or cardiogenic shock • If SBP low, add an inotrope on the short term • “Renal dose dopamine” • Low doses (<2 µg/kg/min iv) • peripheral dopaminergic (DA1) receptors • ↓peripheral VR • vasodilation : renal, splanchnic, coronary, and cerebral vascular beds • ↑ renal blood flow, GFR, diuresis, and Na excretion, • ↑ response to diuretic agents, in renal hypoperfusion and failure • Class of recommendation IIb, level of evidence C

  16. Some in  urea/creatinine/ K+ expected. Small  and asymptomatic-no action  in creatinine up to 50% above baseline or to 266µmol/l  K+≤5.5mmol/l Caution-seek specialist advice if baseline K+≥5.0mmol/l or > 221µmol/l Monitor more frequently in CKD Excessive rise: stop nephrotoxic drugs-NSAIDs, non-essential vasodilators, K+ supplements/sparing diuretics, recheck, reduce diuretic Persists-half ACEI and recheck K+≥5.5mmol/l or if creatinine 100% or to >310µmol/l, stop ACEI/ARB Monitor U&Es closely until creatinine and K+ stable ACEI/ARB and Worsening Renal Function McMurray et al Eur J Heart Fail 2005 7:710

  17. Novel Approaches…

  18. I S R S D S M S K G R L G H G F R C R S S C L K V G K P M S S V Q G Nesiritide Primary Amino Acid Sequence of (hBNP) Clemens LE, Protter AA, et al. J Pharmacol Exp Ther 1998;287:67-71

  19. 35 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) 30 Nesiritide, 0.030 g/kg/min (n = 103) 25 Nesiritide, 0.015 g/kg/min (n = 100) 20 15 10 Cumulative Mortality Rate (%) 5 0 0 30 60 90 120 150 180 Treatment Duration (d) Effect of Short-Term Nesiritide vs Dobutamine on 6-Month Survival Silver MA et al. J Am Coll Cardiol. 2002;39:798–803.

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

  21. Rate of SCr Increase >0.5 mg/dL at Any Time: Nesiritide vs Control References: 1.Sackner-Bernstein JD et al. Circulation 2005;111:1487-1491 2. Data on File, Scios Inc.

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

  23. 30-day mean survival by treatment and nesiritide mortality HR in meta-analysis Sackner-Bernstein JD et al. JAMA 2005; 293:1900-1905.

  24. The future ?

  25. RAPID HFAcute Decompensated Heart Failure • Peripheral veno-venous ultrafiltration • 40 hospitalised patients • Fluid retention • 20 randomised to 8 hours of ultrafiltration plus usual care • Improved symptoms Bart BA et al. J Am Coll Cardiol 2005; 46:2043-2046.

  26. 200 patients, ADHF Randomised to ultrafiltration/iv diuretic Ultrafiltration significantly > fluid loss over 48 hours (p=0.001) Similar effects of creatinine UNLOAD Costanzo M et al. JACC 2007; 49;675

  27. Adenosine A1 Receptor AntagonistIV KW-3902 (Rolofylline) in ADHF (146) with renal dysfunction *p<0.05 vs placebo Givertz MM, JACC 2007;50;1551

  28. AVP-V2 Antagonist TOLVAPTAN“EVEREST” • RCT, n=4133, LVEF<40% • Admitted with HF-persistent “congestion” after standard Rx • Tolvaptan, 30mg/placebo • Primary: all-cause mortality (superiority and noninferiority) and CV death or hospitalization for HF (superiority only). • Secondary : changes in dyspnoea, body weight, and oedema Konstam, M. A. et al. JAMA 2007;297:1319-1331.

  29. “EVEREST” Konstam, M. A. et al. JAMA 2007;297:1319-1331

  30. “EVEREST” Konstam, M. A. et al. JAMA 2007;297:1319-1331

  31. “EVEREST” Konstam, M. A. et al. JAMA 2007;297:1319-1331

  32. Diuretic Resistance in Heart Failure • Common problem • Difficult to manage • Standard measures inadequate • Newer therapies promising • Α1-adenosine receptor antagonists • Ultrafiltration • AVP antagonists

  33. Diuretic Resistance and HF

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