Download Diuretics

Resistencia de Diuretico….ó Resistencia del Doctor
y el Paciente?
Ileana L. Piña, MD, MPH
Professor of Medicine and Epidemiology/Population Health
Albert Einstein College of Medicine
Associate Chief for Academic Affairs – Cardiology
Head Clinical Trials, Cardiology
Montefiore-Einstein Medical Center
Bronx, NY
Outcomes During and After ADHF
 In-hospital1
– Length of stay (mean) 6.2 days
– Mortality rate 4.1%
 Hospital readmissions2
– 20% at 30 days
– 60-90 days
• 24% in Euro-HF
• 30% in OPTIMIZE-HF
– 50% at 6 months
 Longer-term mortality3
– 11.6% at 30 days
– 33.1% at 12 months
1. Fonarow GC, et al. JAMA. 2005;293:572-580.
2. Gheorghiade M, et al. Circulation. 2005;112:3958-3968.
3. Jong P, et al. Arch Intern Med. 2002;162:1689-1694.
2
Important Comorbidities in ADHF
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Hypertension
Coronary artery disease
Myocardial infarction
Stroke/transient ischemia attack
Atrial fibrillation
Chronic renal insufficiency
Hyponatremia
Diabetes
COPD/asthma
Teerlink JR. Diagnosis and Management of Acute Heart Failure. In: Libby P, Bonow RO,
Mann DL, Zipes DP, eds. Braunwald’s Heart Disease. 8th ed. Philadelphia PA: Saunders
Elsevier; 2008:583-610.
3
Diuretics in AHF
 Mechanism of action
– Diuresis (decreased preload)
– ? Pulmonary vasodilation
 Advantages
– Rapid symptomatic improvement
– Decreases volume overload
 Disadvantages
–
–
–
–
Increased neurohormonal activation
Electrolyte disturbances, arrhythmias
Worsen renal function
High diuretic doses associated with increased
hospitalization and mortality
Hunt SA, et al. Circulation. 2009;119:e391-e479.
4
Mechanisms of Sodium and Water Retention in Heart Failure
Chronic Decrease in Cardiac Output
Or Decrease in Peripheral Vascular Resistance
Increased
Cardiac Filling Pressures
Absolute or Relative Decrease
in Arterial Blood Volume
Water
Retention
V2 Receptors
Stimulation
Baroreceptor
Desensitization
Decreased Renal
Perfusion Pressure
Renal
Vasoconstriction
Nonosmotic
AVP Release
Increased Sodium and Water
Retention
Resistance to
Natriuretic Peptides
Failure to Escape
From Aldosterone
Increased
SNS Activity
Increased
RAAS Activity
Decreased GFR
Increased Water and Sodium
Reabsorption
in the Proximal Tubule
Reduced
Distal Delivery of Sodium
Adapted from Schrier RW: J Am Coll Cardiol 2006; 47:1-8
Sodium Reabsorption and
Diuretics Sites of Action in the Nephron
Diuretics: Beneficial Effects
Congestive Heart Failure
Loop Diuretics or
Ultrafiltration
Negative Sodium and
Water Balance
Decreased
Functional Mitral
Insufficiency
Decreased
Ventricular
Dysfunction
Improved Myocardial
Function
Improved Renal Function
Improved
Pulmonary
Congestion
Decreased Cardiac
Filling Pressures
Decreased Ventricular
Wall Stress and
Endomyocardial Ischemia
Pharmacokinetics of Loop Diuretics
Loop
Diuretic
Oral
Bioavailability
(%)
Why is this important in
HF?
1.
Hepatic Congestion
2.
Gut Edema
3.
↓ Gut Blood Flow
Elimination
Half-Life
(hr)
Norm
al
Subje
cts
Patients with
Renal
Insufficiency
Patients
with
Heart
Failure
Furosemide
10-100
1.5-2
2.8
2.7
Bumetanide
80-100
1
1.6
1.3
Torsemide
80-100
3-4
4-5
6
Causes of Diuretic Resistance
 Inadequate Dose
 Patient Non Compliance


– Not taking drug
– High NaCl Intake
Poor Absorption
Impaired Secretion
– Chronic Kidney Disease
– Old Age
– Kidney Transplant
– Chronic Heart Failure
– Drugs
• NSAIDs
• Probenecid







Proteinuria
Hypoproteinemia
Hypotension
Drugs-Direct Inhibitors
– NSAIDs
Diuretic Tolerance
(Structural/Functional
Adaptation) glomerular
hypertrophy
Neurohormonal Activation
‘Cardiorenal Limit’
Inadequate Dosing
AM
PM
+
FENa
Log Diuretic Concentration
Ineffective Effective
Dose
Dose
=0
FENa
Log Diuretic Concentration
Ineffective Effective
Dose
Dose
Ellison DH. Cardiology 2001; 96:132–143
Sodium Intake Influences Diuretic Effect!
Diuretic Secretion Is Impaired in CKD
Uremic anions block diuretic
secretion into the proximal tubule
Diuretics Act from the
tubule lumen
D
Uremic
Loop
Diuretics
Na
K
Cl
Anions
+
K
Na
D
Diuretic
Albumin
Ellison DH. Cardiology 2001; 96:132–143
D
D
Dose-Response Curves
for Loop Diuretics
Ellison DH. Cardiology 2001; 96:132–143
PREVALENCE AND SEVERITY OF
RENAL DYSFUNCTION
IN PATIENTS ADMITTED WITH ADHF
45.7
50
Males
41.2
45
Females
Prevalence (%)
40
30
35
24.9
30
25
20
15
14.6
11.5
10.6
6.6 7.3
7.5
10
5
0
I
II
III
IV
V
Kidney Function Stage
Heywood JT, Fonarow GC, Costanzo MR et al. J Cardiac Fail 2007;13:422-30
Loop Diuretics Stimulate Renin
+
Na
K
Cl
Renin
-
MD
K
Na
LOOP
DIURETIC
+
Na
K
Cl
-
K
TAL
Na
Ellison DH. Cardiology 2001; 96:132–143
Neurohormonal Actions Influencing
Diuretic Action
Glomerulus
Norepinephrine,
Endothelin, AII decrease
renal blood
flow and GFR
Proximal Tubule
AII Increases Na
Reabsorption
Collecting Duct
Aldosterone Increases
Na Reabsorption
Impact of Worsening Renal Function
on Heart Failure Outcomesa
Outcome
RF not worse
RF worse
OR (95% CI)
In-hospital mortality
3%
7%
2.7 (1.6-4.6)
30-day mortality
6%
10%
1.9 (1.3-2.8)
6-month mortality
19%
25%
1.6 (1.2-2.1)
Length of stay, d
6.93
9.14
2.28 (0.25)b
a1681
patients age ≥65 years, discharged with a diagnosis of HF who did not have clear precipitants for
renal dysfunction; bP<.0001.
Krumholz H, et al. Am J Cardiol. 2000;85:1110-1113.
20
Raised Venous Pressure:
A Direct Cause of Renal Sodium Retention
GFR, mL/min
1.4
1.1
0.8
a
High CVP significantly
impairs GFR
aP<.05
0.5
0
6.25 12.5 18.75 25
CVP, mm Hg
vs baseline period
0
CVP, central venous pressure; GFR, glomerular filtration rate.
Adapted from Firth JD, et al. Lancet. 1988;1:1033-1036.
21
Importance of Venous Congestion for
Worsening Renal Function in ADHF
Relative Contributions of CVP and CI to
GFR at Time of Pulmonary Artery Catheter Removal
P=.02
100
GFR, mL/min
80
60
40
20
0
High Cl / Low CVP
20%
Low Cl / Low CVP
32%
High Cl / High CVP Low Cl / High CVP
25%
23%
Error bars represent 95% confidence interval (CI). Cutoff values for CI = 2.4 L/min/m2 and CVP = 8 mm Hg.
CVP, central venous pressure; CI, cardiac index; GFR, glomerular filtration rate.
22
Reproduced with permission from Mullens W, et al. J Am Coll Cardiol. 2009;53:589-596.
Tailoring Therapy
Clinical Pearls
● Although the concept was ignored in the guidelines and in
recent trial designs, targeting treatment to pathophysiology
would be logical
– Analogy: O2 is good for all pneumonia with hypoxia,
but antibiotics must be tailored to the organism
● Similarly, although furosemide and/or nitrates may help all
ADHF symptomatically, beyond acute reduction in
pulmonary venous pressure, therapy should ideally target
the cause of the decompensation
Courtesy of Steven R. Goldsmith, MD.
23
Therapy: No new therapies approved since
nesiritide
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
Diuretics!
Diuretics!
Renal replacement Rx
Vasodilators
– Nitrates
– Nesiritide
– Nitroprusside
 Inodilators
– Milrinone
 Inotropes
– Dobutamine, dopamine
 Novel agents
– Serelaxin
Diuretics in Hospitalized Patients
I IIa IIb III
I IIa IIb III
Patients with HF admitted with evidence of significant fluid
overload should be promptly treated with intravenous loop
diuretics to reduce morbidity.
If patients are already receiving loop diuretic therapy, the
initial intravenous dose should equal or exceed their
chronic oral daily dose and should be given as either
intermittent boluses or continuous infusion. Urine output
and signs and symptoms of congestion should be serially
assessed, and the diuretic dose should be adjusted
accordingly to relieve symptoms, reduce volume excess,
and avoid hypotension.
Diuretics in Hospitalized Patients (cont.)
I IIa IIb III
I IIa IIb III
The effect of HF treatment should be monitored with
careful measurement of fluid intake and output, vital signs,
body weight that is determined at the same time each day,
and clinical signs and symptoms of systemic perfusion and
congestion. Daily serum electrolytes, urea nitrogen, and
creatinine concentrations should be measured during the
use of intravenous diuretics or active titration of HF
medications.
When diuresis is inadequate to relieve symptoms, it is
reasonable to intensify the diuretic regimen using either:
a. higher doses of intravenous loop diuretics.
b. addition of a second (e.g., thiazide) diuretic.
The Hospitalized Patient
Intensifying the Diuretic Regimen
When diuresis is inadequate to relieve congestion, as evidence by
clinical evaluation, the diuretic regimen should be intensified by
using one of the following
I IIa IIb III
 Higher doses of loop diuretics
 Adding a second diuretic (such as metolazone,
spironolactone, or IV chlorothiazide)
 Continuous infusion of a loop diuretic
Hunt SA, et al. Circulation. 2009;119:e391-e479.
27
Patients' Global Assessment of Symptoms
during the 72-Hour Study-Treatment Period.
Felker GM et al. N Engl J Med 2011;364:797-805.
Kaplan–Meier Curves for the Clinical Composite End Point of
Death, Rehospitalisation, or Emergency Department Visit.
Felker GM et al. N Engl J Med 2011;364:797-805.
Mean Change in Serum Creatinine Level.
Felker GM et al. N Engl J Med 2011;364:797-805.
Secondary End Points for Each Treatment Comparison.
Felker GM et al. N Engl J Med 2011;364:797-805.
Conclusions
 Among patients with acute decompensated heart failure, there
were no significant differences in patients' global assessment of
symptoms or in the change in renal function when diuretic
therapy was administered by bolus as compared with continuous
infusion or at a high dose as compared with a low dose.
Diuretics in Hospitalized Patients (cont.)
I IIa IIb III
Low-dose dopamine infusion may be considered
in addition to loop diuretic therapy to improve
diuresis and better preserve renal function and
renal blood flow.
An approach to treating patients with acute
heart failure who are diuretic resistant
Maaten J M, et al. Nat Rev Cardiol. 2015 Mar;12(3):184-192.
Vasodilators in AHF
 Mechanism of action
– cGMP-mediated venous and/or arterial vasodilation
(reduces preload and/or afterload)
 Advantages
– Rapid symptomatic improvement
– Relatively safe
 Disadvantages
–
–
–
–
–
Minimal effect in increasing cardiac output
Hypotension, headache
Tolerance/tachyphylaxis (frequent titration)
Invasive monitoring, cyanide toxicity (nitroprusside)
Unclear effect on hospitalization and mortality
Hunt SA, et al. Circulation. 2009;119:e391-e479.
35
HFSA 2010 Practice Guideline
ADHF — IV Vasodilators
Recommendation 12.17
In the absence of symptomatic hypotension, IV nitroglycerin,
nitroprusside, or nesiritide may be considered as an addition to
diuretic therapy for rapid improvement of congestive symptoms in
patients admitted with ADHF (Strength of Evidence = B)
– Frequent blood pressure monitoring is recommended with these
agents (Strength of Evidence = B)
– These agents should be decreased in dosage or discontinued if
symptomatic hypotension or worsening renal function develops
(Strength of Evidence = B)
– Reintroduction in increasing doses may be considered once
symptomatic hypotension is resolved (Strength of Evidence = C)
Lindenfeld J, et al. J Card Fail. 2010;16:e1-e194.
36
HFSA 2010 Practice Guideline
ADHF — IV Vasodilators
Recommendation 12.18
IV vasodilators (IV nitroglycerin or nitroprusside) and diuretics are
recommended for rapid symptom relief in patients with acute
pulmonary edema or severe hypertension (Strength of Evidence = C)
Recommendation 12.19
IV vasodilators may be considered in patients with ADHF who have
persistent severe HF despite aggressive treatment with diuretics
and standard oral therapies
– Nitroprusside (Strength of Evidence = B)
– Nitroglycerine, nesiritide (Strength of Evidence = C)
Lindenfeld J, et al. J Card Fail. 2010;16:e1-e194.
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Nitrates vs Diuretics in Fulminant
Pulmonary Edema
Primary
Outcome
Predominant
Isosorbide
Dinitrate
(n=52)
Predominant
Furosemide
(n=52)
P Value
Died
1 (2%)
3 (6%)
.61
Required
mechanical
intervention
7 (13%)
21 (40%)
.0041
MI
9 (17%)
19 (37%)
.047
Any adverse
event
13 (25%)
24 (46%)
.041
Cotter G, et al. Lancet. 1998;351:389-393.
38
Inotropes/Inodilators in ADHF
 Mechanism of Action
– Increased cAMP via b-adrenergic receptors
(dobutamine) or PDE inhibition (milrinone)
– Increased myocardial contractility and peripheral
vasodilation
 Advantages
– Increased cardiac output and organ perfusion
 Disadvantages
–
–
–
–
–
Increased myocardial oxygen consumption
Unpredictable hypotension (milrinone)
Tolerance
Increased arrhythmias
Increased mortality
Teerlink JR, et al. Heart Fail Rev. 2009;14:243-253.
39
HF Etiology and Response to Milrinone
in ADHF (OPTIME-CHF)
1
0.98
Survival
0.96
0.94
0.92
Milrinone, ischemic
Milrinone, nonischemic
Placebo, ischemic
Placebo, nonischemic
0.9
0.88
0.86
0
10
20
30
40
50
60
Days
Reproduced with permission from Felker GM, et al. J Am Coll Cardiol. 2003;41:997-1003.
40
Avoiding Renal Failure
Clinical Pearls
● Both persistent congestion and worsening renal failure are
very poor prognostic features after treatment for ADHF
● Recent data may be tipping toward greater importance of
decongestion, so long as worsening renal failure is transient
● Comparative trials of renal-sparing vs loop-diuretic based
regimens are however limited at present
● In theory, decongestion without some of the adverse renal
and neurohormonal effects of furosemide would be desirable
Courtesy of Steven R. Goldsmith, MD.
41
Assessing Adequacy of Treatment
Clinical Pearls
● Ideally, patients leave the hospital completely
decongested, with normalized cardiac filling pressure and
arterial pressure
● Registry and even trials data suggest we are not meeting
that goal consistently
● We are not sure of how to assess the adequacy of
decongestion in many patients, without direct
measurement of filling pressures, and even that may not
be completely satisfactory (ESCAPE trial)
Courtesy of Steven R. Goldsmith, MD.
42
Use of Pulmonary Artery Catheterization:
No Effect on Mortality
and Hospitalization (ESCAPE)
Cumulative Proportion
1.0
PAC + Clinical Assessment (n=206)
Clinical Assessment Only (n=207)
0.8
0.6
0.4
0.2
0
30
60
90
120
150
180
Days Well (not dead or hospitalized)
Reproduced with permission from The ESCAPE Investigators and ESCAPE Study Coordinators.
JAMA. 2005;294:1625-1633.
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Hyponatremia in ADHF
44
Hyponatremia Classification
● Depletional hyponatremia occurs due to loss of solute
relative to total body water
● Dilutional hyponatremia occurs due to excess water
relative to total body sodium (which may be normal in
euvolemic states, or increased, in hypervolemic states)
Verbalis JG. Best Pract Res Clin Endocrinol Metab. 2003;17:471-503.
45
Hyponatremia: Pathophysiology
● Dilutional hyponatremia is due primarily to excessive
levels of circulating arginine vasopressin (AVP), the
major hormone regulating total body water1 and the
RAAS system
● In ADHF, hyponatremia is nearly always dilutional since
total body volume is nearly always increased in this
situation, meaning that excessive circulating AVP is the
primary cause2
● Reducing AVP levels or antagonizing the renal receptor
for AVP are therefore the most rational approaches to
treating hyponatremia in ADHF1,2
1. Adrogue HJ. Am J Nephrol. 2005;25:240-249.
2. Douglas I. Cleve Clin J Med. 2006;73(suppl 3):S4-S12.
46
AVP Levels Are Elevated in Patients
With Hypo-osmolality and CHF
19.2
14.0
13.0
Plasma AVP, pg/mL
No diuretics
(n=14)
Normal Range
15.0
12.0
4.0
3.0
Taking
diuretics
(n=23)
2.0
1.0
0.5
0.0
250
260
270
280
290
300
Plasma Osmolality, mOsm/kg of Water
Reproduced with permission from Szatalowicz VL, et al. N Engl J Med. 1981;305:263-266.
47
Furosemide Accelerates LV Systolic Dysfunction
placebo-treated (blue line)
furosemide-treated animals (red line)
p = 0.038
McCurley, J. M. et al. J Am Coll Cardiol 2004;44:1301-1307
P = 0.013
P < 0.05
Cosin J et al. Eur J Heart Fail. 2002; 4:507-13
Lopez B et al. JACC 2004; 43: 2028-35
Relation Between Dose of Loop Diuretics and Outcomes in a Heart
Failure Population: Results of the ESCAPE Trial
Hasselblad V et al. Eur J Heart Fail 2007; 9: 1064-9
My “cocktail”
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
Constant infusion loop diuretic 5, 10 mg/hr with loading dose
Slow to allow refill time from extracellular space
Gentler on the kidney
If significant peripheral (3rd space edema), add spironolactone
– ½- 1 hr pre loop diuretic
– Follow K carefully
– Can increase to bid or tid if K is stable
 Add nitrates, oral, nitropaste or IV nitroglycerin.
 In outpatient, increases in ACEI/ARB, automatic decrease in daily diuretic
– Address the RAAS increase
Gracias!