Journal Article:
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
- ?higher doses of mineralocorticoid antagonists to dec. congestion in dec HF?
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