Journal Article:

Diuretic_Treatment_HF

Summary:

Diuretic Treatment in Heart Failure

David H. Ellison, MD and G. Michael Felker, MD

Use:

• Diuretics are cornerstone of management of heart failure
• Evidence, particularly from large, well-controlled clinical trials, guiding the use of diuretics is lacking

Pharmacologic Characteristics of Loop Diuretics:

• Prototypical loop diuretics = furosemide, bumetanide, torsemide
• Loops are mostly protein bound (>90%), therefore volume of distribution is limited
• MOA: bind sodium-potassium-chloride cotransporters (NKCCs), blocking ion transport along loop of Henle; transporter is responsible for reabsorption of approx. 25% filtered Na-Cl
  • Other effects: stimulated renin section, inhibition of tubuloglomerular feedback
• S/E = ototoxicity = ML because of sodium-potassium-chlorite symporter isoform (NKCC1) expressed in ear; Vasodilation due to NKCC1 in vascular smooth-muscle cells; also renal effects; s/e of high-dose IV loop diuretics = inc. or dec. in arterial pressure, inc. or dec. in stroke volume, dec. renal blood flow

Pharmacokinetic Characteristics of Loop Diuretics:

• “Threshold drugs” – inc. dose beyond a “ceiling” does not increase the effect
• Oral furosemide = limited, variable bioavailability: mean = 50% though range = 10-90%; food intake delays absorption
• Preserved kidney fx = IV dose of furosemide is 2x as potent on a per-mg basis as oral doses
• In Acute Decompensated HF = IV dose likely more effective than oral dose
• Bumetanide, torsemide = higher, more consistent oral bioavailability than furosemide (>90%); oral and IV doses are similar
• T1/2 of torsemide = 6h, furosemide = 2.7h, bumetanide = 1.3h
  • Systematic analysis of torsemide vs. furosemide suggested torsemide reduced hospital readmissions for heart failure à good Q for future clinical trial
• Goal of Loop Diuretics in HF:
  • urinary excretion of NaCl
  • Negative short-term NaCl and H20 balance (decongestion)
  • Reduce ECF volume
• Patients may experience “post-diuretic sodium retention” – low sodium excretion after diuretic (initially inc. excretion of NaCl)
  • Important for patients to adhere to low-Na diet, or else Na-intake can offset natriuresis
• “Braking Phenomenon” – ECF dec., natriuretic response to each dose of diuretic decreases

Use of Loop Diuretics in Patients with Acute Decompensated Heart Failure:

• Diuretic use is a Class I recommendation based on Level B or C evidence
• Association b/w high dose diuretics and poor outcomes?
• Diuretic Optimization Strategies Evaluation (DOSE) trial – approach to diuretic dosing and route of administration in those with ADHF:
  • 2×2 factorial design (furosemide IV twice-daily bolus vs. continuous infusion; low dose PO (patients previous oral dose) or high dose PO (2.5x patients previous); all groups received IV bolus q12h and continuous infusion (furosemide vs. saline placebo)
  • 308 pts randomly assigned (factorial double-dummy design)
  • PO Group
    • No statistical sig in assessment of sx
    • High dose group = more favorable outcomes in relief from dyspnea, change in weight, net fluid loss; High dose group = more likely to have worsening renal function;
    • Post-hoc analysis = initial inc. in serum Cr associated with better long-term clinical outcome
    • Although observational data suggests high dose diuretics = inc. mortality; DOSE trial suggests high dose approach = reasonable!
  • IV Group
    • No statistical sig b/w bolus and continuous infusion in patients global assessment of sx and change in serum Cr at 72h
    • These data DO NOT support use of continuous infusion of diuretics for acute decompensated HF; though authors admit several limitations of their study
    • IV boluses at daily dose 2.5x oral dose is reasonable initial strategy, but consider the clinical picture (diuretic resistance, cardiorenal syndrome, right ventricular dysfx = maybe IV better…)

Adjuncts to Diuretic Treatment:

• Hyponatremia is common in HF, portends poor prognosis
• Tolvaptan = oral vasopressin-2 receptor antagonist – inhibit action of ADH and inc. excretion of free water
  • Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial – evaluated patients admitted for HF (+/- hyponatremia) – did not show superiority of tolvapton over placebo with long-term clinical outcomes. May help volume status in initial days.
• Dopamine = inc. renal blood Q and excretion of urinary sodium at low doses (?augment natriuresis)
  • Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial; furosemide + dopamine infusion, nesiritide, or placebo; neither drug affected urine volume, change in cystatin C level over 72h period. Dopamine caused Tachycardia (stat sig)
  • Post-Hoc analysis: effects of LDDopamine differed according to HF subtype: pts with HFrEF – enhanced decongestion and improved prognosis à future study
• Spironolactone (mineralocorticoid antagonists) at low doses decrease mortality in patients with HFrEF
  • ?higher doses of mineralocorticoid antagonists to dec. congestion in dec HF?
    • ATHENA-HF study (Study of High-dose Spironolactone vs. Placebo Therapy in Acute HF): High dose spiro vs. low dose – did not improve decongestion measured by change in N-terminal Pro-B-type natriuretic peptide level, symptom improvement

Diuretic Resistance and the Cardiorenal Syndrome:

• Diuretics don’t achieve decongestion despite max dose
• Max dose furosemide = 250mg
• Diuretic-resistant = high risk of illness, death
• If diuretic resistant with kidney dysfx = cardiorenal syndrome
  • 2’ to nephron remodeling by various mechanisms

Treating Diuretic Resistance:

• Failure of diuretics to achieve decongestion
• Low urine sodium concentration despite max dose diuretics
• Classically:
  • Continuous IV diuretic therapy
• Evidence:
  • Post-Hoc analysis = stepped care, pharmacologic approach
• ACEI/ARB: direct natriuretic effects by inhibiting sodium reabsorption along nephron, can inhibit natriuresis because of lower arterial pressure
  • In HFrEF: typically continued
  • In HFpEF: d/c b/c possibly detrimental
• Blocking sodium chloride reabsorption in distal nephron (metolazone, other thiazide-types) though haven’t been evaluated in clinical trials; ?future = low-dose sequential blockade (along the nephron)
  • But combo LOOP + Thiazide = natriuresis, kaliuresis = MONITORING
• Oral metolazone + loop diuretic may be as effective as IV chlorothiazide
• CAI = good choice if metabolic alkalosis

Other Approaches and Future Directions:

• ?Extracorporeal ultrafiltration
  • Trial b/w UF and pharm therapy = similar fluid removal; more renal dysfx and a/e in UF
  • UF primarily indicated when dialytic treatment is indicated in pts with combined HF and renal failure
• ?Combo Hypertonic saline w/ High Dose loop diuretics
  • Has not been tested in robust trials
• ?SubQ Furosemide – currently being tested in a multicenter, RCT