Journal of the American College of Cardiology Vol. 56, No.

19, 2010
© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2010.06.034

STATE-OF-THE-ART PAPERS

Combination of Loop Diuretics With

Thiazide-Type Diuretics in Heart Failure
Jacob C. Jentzer, MD,* Tracy A. DeWald, RD, PHARMD, BCPS,*† Adrian F. Hernandez, MD*‡§
Durham, North Carolina

Volume overload is an important clinical target in heart failure management, typically addressed using loop di-
uretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant
doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type di-
uretic to produce diuretic synergy via “sequential nephron blockade,” first described more than 40 years ago.
Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this
strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summa-
rize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure
in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy
using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight
loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension,
and worsening renal function. We provide considerations about prudent use of this therapy and review potential
misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clini-
cal trials for this commonly used therapy. (J Am Coll Cardiol 2010;56:1527–34) © 2010 by the American Col-
lege of Cardiology Foundation

Heart failure is the leading hospital discharge diagnosis uating the efficacy or safety of diuretics (6). Before the
among elderly Americans, accounting for more than DOSE trial, many thought patients with acute heart failure
1 million hospital admissions each year in the U.S. (1). receiving high doses of LD were at increased risk of serious
Prognosis after heart failure hospitalization is poor, with adverse events (7) and renal failure (8). Patients with heart
50% of patients rehospitalized within 6 months and 25% to failure who are resistant to LD have poor outcomes, which
35% mortality at 1 year (2). Despite several clinical trials, no may be a function of their more severe underlying disease
single pharmacologic therapy has been clearly shown to process (9).
reduce mortality or rehospitalization rates in acute heart
failure (3). Congestion in acute heart failure syndromes Overcoming Diuretic Resistance
appears to be more complicated than fluid accumulation in Edematous States
alone (4,5). The vast majority of patients admitted for
Fluid overload refractory to conventional treatment with
decompensated heart failure are treated primarily with
LD can complicate acute or chronic heart failure man-
intravenous loop diuretics (LD), and until the recently
agement. Diuretic resistance in heart failure results from
completed DOSE (Diuretic Optimization Strategies Eval-
an interaction between the pathophysiology of sodium
uation) trial, there were limited prospective trial data eval-
retention in heart failure and the renal response to
diuretic therapy (Fig. 1) (10). By eliciting significant
counter-regulatory responses during acute and chronic
From the *Department of Medicine, Duke University School of Medicine, Durham,
North Carolina; †Division of Clinical Pharmacology, Department of Medicine, Duke use, several effects such as the “braking phenomenon,”
University School of Medicine, Durham, North Carolina; ‡Division of Cardiology, post-diuretic effect, rebound sodium retention, and renal
Department of Medicine, Duke University School of Medicine, Durham, North adaptation lead to diuretic resistance. The braking phe-
Carolina; and the §Duke Clinical Research Institute, Duke University Medical
Center, Durham, North Carolina. This project was supported by grant number nomenon describes an acute reduction in diuretic efficacy
U18HS016964 from the Agency for Healthcare Research and Quality (AHRQ). The with repeated LD dosing, while the post-diuretic effect
content is solely the responsibility of the authors and does not necessarily represent the refers to increased sodium retention after the LD has
official views of the AHRQ. Dr. Hernandez was supported by American Heart
Association Pharmaceutical Roundtable grant 0675060N. Dr. Hernandez reported worn off. Rebound sodium retention occurs when chronic
receiving research support from Johnson & Johnson, Merck & Co., and Proventys and LD use leads to increased distal nephron sodium reab-
honoraria from AstraZeneca, Amgen, Corthea, and Medtronic. All other authors sorption. Renal adaptation occurs with prolonged expo-
report that they have no relationships to disclose.
Manuscript received February 17, 2010; revised manuscript received April 30, sure to LD and is described as hypertrophy and hyper-
2010, accepted June 1, 2010. function of distal tubule cells causing increased local sodium
1528 Jentzer et al. JACC Vol. 56, No. 19, 2010
Combination Diuretic Therapy in Heart Failure November 2, 2010:1527–34

Abbreviations uptake and aldosterone secretion, differences in the half-life of intravenous torsemide and
and Acronyms which markedly limits the re- furosemide in patients with heart failure have been docu-
sponse to LD (11,12). Distal tu- mented (14). To overcome diuretic resistance, a more
CDT ⴝ combination diuretic
therapy bule hypertrophy also appears to frequent administration schedule might be preferred for
LD ⴝ loop diuretic(s)
be an important contributor to intravenous furosemide with a mean half-life of 1.5 h
rebound sodium retention and compared with intravenous torsemide with a mean half-life
TD ⴝ thiazide-type
diuretic(s)
reduced response to chronic LD of 6.3 h. Ideally, critical evaluations of the effectiveness of a
therapy over time (13). The ac- drug regimen occur at steady state when the rate of drug
tivities of different diuretics administration is equal to the rate of drug elimination. In
should be considered to overcome the potential problems most clinical situations, steady state can be assumed after 4
with diuretic resistance (Fig. 1). half-lives. Similarly, in most clinical situations, it can be
Consideration of pharmacokinetic parameters of LD assumed that all drug has been eliminated after 4 half-lives
therapies may help to optimize strategies for overcoming have passed without further drug administration. If the
diuretic resistance. Increasing LD doses is often considered dosing interval for intravenous LD therapies extends be-
initially to increase plasma drug concentrations and hope- yond 4 half-lives, it is expected that there will be periods of
fully enhance LD effectiveness. Additional consideration time when no drug is available for pharmacologic activity
may be given to drug half-life. For example, significant and suboptimal effect may be observed. Thus, optimization

Figure 1 Diuretic Resistance and the Nephron

Sites of diuretic action and sodium retention with suggested strategies to overcome diuretic resistance. Sodium delivery into tubular fluid is determined by glomerular
filtration rate (GFR). Percentage of filtered sodium reabsorbed in each nephron segment is denoted in parentheses. Proximal convoluted tubule reabsorbs the majority of
filtered sodium and proximal reabsorption is increased in sodium-retaining states under the control of neurohormones (alpha-1 adrenergic, angiotensin-II), producing the
post-diuretic effect. Loop of Henle is the site of action of loop diuretics (LD) and absorbs most of the sodium that escapes the proximal tubule; braking effect appears to
occur here due to up-regulation of the Na/K/Cl cotransporter after exposure to LD. Distal convoluted tubule reabsorbs a lesser amount of filtered sodium via NaCl
cotransporter (inhibited by thiazide-type diuretics [TD]) but size and function may increase dramatically after chronic LD exposure, accounting for rebound sodium reten-
tion. Distal nephron collecting duct is the site of regulated sodium and water reabsorption under control of aldosterone and vasopressin via epithelial sodium channels
(ENaC) and aquaporins, respectively. Multiple mechanisms of diuretic resistance may occur in a single patient, requiring a systematic approach to diuretic therapy.
Figure illustration by Craig Skaggs based on the author’s description and an example nephron from Ernst ME, Moser M. Use of diuretics in patients with hypertension.
N Engl J Med 2009;36:2153– 64. ACEI ⫽ angiotensin-converting enzyme inhibitor; ARB ⫽ angiotensin-receptor blocker.
JACC Vol. 56, No. 19, 2010 Jentzer et al. 1529
November 2, 2010:1527–34 Combination Diuretic Therapy in Heart Failure

Mechanism
Table 1 of Action of Diuretic
Mechanism of ActionClasses
of Diuretic Classes

Drug Class Examples Mechanism of Action

Carbonic anhydrase inhibitors Acetazolamide Inhibition of proximal convoluted tubule sodium bicarbonate reabsorption
Loop diuretics Furosemide Inhibition of Na/K/2Cl cotransporter in thick ascending loop of Henle
Bumetanide
Torsemide
Thiazide-type diuretics Hydrochlorothiazide Inhibition of Na/Cl cotransporter in distal convoluted tubule
Metolazone
Potassium-sparing diuretics Amiloride Inhibition of aldosterone-responsive epithelial Na channel (ENaC) in distal nephron ⫹ collecting tubule
Triamterene
Aldosterone antagonists Spironolactone Inhibition of aldosterone receptors in distal nephron ⫹ collecting tubule, reducing Na channel and Na/K ATPase
Eplerenone
Vasopressin antagonists Conivaptan* Inhibition of V2 receptors in distal nephron ⫹ collecting tubule, reducing aquaporin (water) channel density
Tolvaptan

*Conivaptan has nonselective V1A/V2 antagonism.

of LD regimens may be considered as a possibility to daily as well as limited duration (3 days) versus indefinite
overcome apparent diuretic resistance. duration (physician’s discretion) of combination diuretic
After optimization of LD, other causes of diuretic resis- therapy (CDT). Both drugs significantly augmented diure-
tance should be considered, particularly braking and post- sis and produced a similar (⬎5 kg) mean weight loss over 5
diuretic effects. Physiologically, sequential nephron block- to 6 days; diuresis continued for the same amount of time
ade by addition of a second diuretic class to ineffective regardless of CDT treatment duration. Clinical response
optimized LD therapy can address other forms of diuretic occurred in 92.5%, with symptomatic improvement allow-
resistance. By blocking distal tubule sodium reabsorption, ing hospital discharge in 90% of patients. Metolazone had
thiazide-type diuretics (TD) can antagonize the renal ad- greater adverse effects on potassium levels and renal function
aptation to chronic LD therapy and potentially improve than bendroflumethiazide, but no clinical adverse effects
diuretic resistance due to rebound sodium retention (12,15). were reported; nearly two-thirds of patients developed
Several of the other mechanisms of action of different significant hypokalemia (serum potassium ⬍3.5 mEq/l).
diuretic classes are summarized in Table 1 (16). Other observational studies have shown the addition of
moderate-dose TD often induced diuresis in patients resis-
Combination Diuretic Therapy tant to very large doses of LD, with or without potassium-
to Overcome Resistance to LD sparing diuretics (43). Outpatients previously dependent on
intermittent intravenous LD could be maintained on oral
The earliest studies examining the addition of TD to LD in diuretics after addition of metolazone (35). The majority of
patients with resistant edema due to heart failure or other inpatients with acute heart failure refractory to maximal
edematous states date back more than 40 years to the early therapy, including intravenous LD, responded to the addi-
days of diuretic therapy (17). Despite more than 50 pub- tion of low-dose metolazone within 48 to 72 h, allowing
lished reports, the experience is limited to 300 heart failure hospital discharge; metolazone nonresponders had a partic-
patients (Table 2) (17– 45), raising many questions about ularly poor prognosis (37). In a small study, the addition of
this potent diuretic combination. The aggregate body of chlorothiazide to LD during an episode of decompensated
literature is limited by the small size of studies, study design heart failure allowed clinical stabilization and remained
with lack of control groups, heterogeneous patient popula- effective for prevention of edema reaccumulation after hos-
tions, wide variation in diuretic regimens, and focus on pital discharge for ⬎2 years in some patients (42).
physiologic rather than clinical outcomes. In fact, most
studies have evaluated weight loss or clearance of persistent TD in Combination Therapy: Common
edema as the end point. The main findings date back to a Misconceptions and Evidence of a Class Effect
series of randomized, cross-over laboratory studies per-
formed in the early 1970s that showed that TD increased Although there are some commonly held beliefs about TD
urine sodium excretion and urine volume compared with in CDT, the literature varies regarding many of these
increasing the LD dose (21,25). concepts. Metolazone is touted as being superior to other
Among the largest randomized clinical trials was a TD for CDT, possibly due to inhibition of proximal tubule
40-patient study comparing 2 different TD added to exist- function (46). Direct comparison of metolazone with ben-
ing LD therapy (41). In a 2 ⫻ 2 factorial design, in patients droflumethiazide in a randomized, double-blind trial found
with New York Heart Association functional class III/IV no superiority of metolazone (41); comparison of quinetha-
heart failure symptoms despite intravenous furosemide 80 zone (metolazone’s parent compound) with bendroflume-
mg twice daily were randomized to the addition of ben- thiazide revealed similar effects of both drugs (21). How-
droflumethiazide 10 mg daily versus metolazone 10 mg ever, a response to metolazone plus furosemide was
 1530
Summary
Table 2 of Summary
Reviewed of
Studies in Heart
Reviewed Failure
Studies Patients
in Heart Failure Patients

First Author (Ref. #), Year Patients Design TD Dose LD Dose Benefits Adverse Events

Combination Diuretic Therapy in Heart Failure

Jentzer et al.
Robson et al. (18), 1964 1 CHF Observational HCTZ 100 mg IV FSM 50–100 mg IV ⫹ None Not reported
1–5 mg/min
Dettli and Spring (17), 1966 18 mixed Observational HCTZ 200 mg FSM 30–240 mg/day Improved diuresis, similar to 4⫻ higher Hypochloremic alkalosis ⫹ hypokalemia
edematous FSM dose
Olesen et al. (19), 1970 24 CHF Randomized QEZ 50–100 mg/day FSM 40–80 mg/day Superior diuresis to doubled FSM dose in Hypokalemia (⫺0.5 mEq/l) bigeminy
active-control mild CHF only
Olesen et al. (20), 1971a 12 CHF Randomized QEZ 50 mg/day FSM 40 mg/day Doubled UNa, mean weight loss 0.5 kg/day Not reported
active-control
Olesen et al. (21), 1971b 24 CHF Randomized QEZ 50 mg/day FSM 80 mg BID Doubled UNa, weight loss ⬃0.7–0.8 kg/day Hypokalemia (⫺0.3 mEq/l)
active-control BDFZ 5 mg/day
Beck and Asscher (22), 1971 1 CHF Observational MTZ 5 mg/day FSM 80 mg/day Clearance of edema Hypokalemia
Gunstone et al. (23), 1971 13 CHF Observational MTZ 2.5–10 mg/day FSM 120–400 mg/day ⱖ2 kg weight loss over 4 days in ⬎2/3 overall Azotemia in most patients, hypokalemia
Asscher (24), 1974 4 CHF Observational MTZ 5 mg/day FSM ⱖ500 mg/day Mean weight loss 8.1 kg Hypokalemia
Sigurd et al. (25), 1975 18 CHF Randomized BDFZ 5 mg/day BMT 2 mg BID Doubled UNa, mean weight loss 0.8 kg/day Hypokalemia (⫺0.45 mEq/l)
active-control
Epstein et al. (26), 1977 1 CHF Observational MTZ ⱖ5 mg/day FSM 160 mg PO BID Increased UNa even with severely reduced GFR Hypokalemia
Ram and Reichgott (27), 1977 5 CHF ⫹ CKD Observational MTZ 5 mg/day FSM 160–320 mg/day Mean weight loss 4.4 kg Hypokalemia (⫺0.3 mEq/l), creatinine 1 28%
Sigurd and Olesen (28), 1978 18 CHF Randomized BDFZ 5 mg/day BMT 2 mg BID Tripled UNa, similar effect to aminophylline None
active-control 200 mg BID
Furrer et al. (29), 1980 11 ADHF Observational MTZ ⱖ2.5 mg/day FSM 40–370 mg/day Mean 6.7 kg weight loss Excessive/uncontrolled diuresis
Ghose and Gupta (30), 1981 3 CHF Observational MTZ 2.5–5 mg/day Various ⬃0.3–0.6 kg/day weight loss Not reported
Allen et al. (31), 1981 4 CHF Observational MTZ 5 mg/day FSM 1–2 g/day 8–13L diuresis over 4–5 days Hypokalemia
Bamford (32), 1981 1 CHF Observational MTZ 5 mg QOD FSM 500 mg/day 13 kg weight loss Not reported
Grosskopf et al. (33), 1986 10 ADHF Randomized MTZ 5 mg/day FSM 120 mg/day IV Improved diuresis, weight loss ⬃2.2 kg Hypokalemia (⫺0.4 mEq/l)
active-control over 3 days
Gage et al. (34), 1986 14 CHF Observational MTZ 2.5 mg QOD up to FSM 160 mg/day Mean 4.4 kg weight loss ⫹ edema clearance Hypokalemia (⫺0.6 mEq/l), BUN 1 ⬃33%
15 mg/week
Aravot et al. (35), 1989 12 CHF Observational MTZ 2.5–5 mg FSM 160 mg/day Eliminated need for IV diuresis Not reported
2⫻/week
Friendland and Ledingham (36), 1989 1 ADHF Observational MTZ 5–10 mg/day FSM 240 mg/day IV 16 kg weight loss Not reported
Kiyingi et al. (37), 1990 10 CHF Observational BDFZ 10 mg/day FSM 200–400 mg/day IV Mean weight loss 7.7 kg Hypokalemia (⬍2.9 mEq/l) in 20%
Channer et al. (38), 1990 17 ADHF Observational MTZ 1.25–10 mg/day FSM 250–500 mg/day PO Responders (71%) had mean 8.3 kg Hypokalemia, creatinine 1 25%
weight loss ⫹ d/c home
Kröger et al. (39), 1991 10 ADHF Observational MTZ 2.5–5 mg/day FSM 80–500 mg/day Mean 8.9 kg weight loss Hyponatremia, hypokalemia
Dormans and Gerlag (40), 1993 8 CHF Observational HCTZ 25–100 mg/day FSM 500– 4000 mg/day Doubled UNa, mean 1.3 kg/day weight loss Creatinine 1 50%, ClCr 2 33%, hypokalemia
Channer et al. (41), 1994 40 ADHF Randomized MTZ 10 mg/day FSM 80 mg IV BID 5–5.6 kg mean weight loss, hospital d/c Hypokalemia (⬍3.5 mEq/l) in 65%
active-control BDFZ 10 mg/day in 90%
Mouallem et al. (42), 1995 32 ADHF Observational CTZ 500 mg/day FSM 160–320 mg/day Mean 4.8 kg weight loss, clearance of edema Hypokalemia (⫺0.4 mEq/l)
Dormans and Gerlag (43), 1996 20 ADHF Observational HCTZ 25–100 mg/day FSM 250–4000 mg/day Doubled UNa, mean weight loss 6.7 kg, Hypokalemia (⫺0.8 mEq/l),
d/c home in 70% persistent dehydration

November 2, 2010:1527–34
JACC Vol. 56, No. 19, 2010
Vanky et al. (44), 1997 20 post-CABG Observational HCTZ 50 mg/day ⫹ FSM 80 mg/day Mean 2.3 kg weight loss after one dose None
amiloride 5 mg/day
Rosenberg et al. (45), 2005 21 CHF Observational MTZ 2.5–5 mg/day FSM mean 260 mg/day Mean 2 kg weight loss ⫹ 10/8 mm Hg BUN 1 58%, hypokalemia (⫺0.8 mEq/l),
BP reduction creatinine 1 27%

Some studies included patients with diagnosis other than heart failure.
ADHF ⫽ acute decompensated heart failure (inpatients); BDFZ ⫽ bendroflumethiazide; BID ⫽ twice daily; BMT ⫽ bumetanide; BP ⫽ blood pressure; BUN ⫽ blood urea nitrogen; CABG ⫽ coronary artery bypass grafting; CHF ⫽ chronic heart failure (outpatients); CKD; ⫽
chronic kidney disease; ClCr ⫽ creatinine clearance; CTZ ⫽ chlorothiazide; d/c ⫽ discharge; FSM ⫽ furosemide; GFR ⫽ glomerular filtration rate; HCTZ ⫽ hydrochlorothiazide; IV ⫽ intravenous; MTZ ⫽ metolazone; PO ⫽ oral; QEZ ⫽ quinethazone; QOD ⫽ every other day;
UNa ⫽ urine sodium.
JACC Vol. 56, No. 19, 2010 Jentzer et al. 1531
November 2, 2010:1527–34 Combination Diuretic Therapy in Heart Failure

documented in a single patient resistant to chlorothiazide chronic heart failure, but may be a marker of increased
plus furosemide (24). Numerous TD have been evaluated in disease severity (9). The anticipated benefits of CDT at a
combination with various LD with similar results overall, low cost make this a potentially attractive therapeutic
and no clear evidence that any single TD is superior, option; increased urine sodium concentration with CDT
suggesting a class effect. The most commonly used TD were overcomes 1 of the limitations of LD monotherapy for
metolazone, bendroflumethiazide, quinethazone, and hy- fluid removal. CDT has not been directly compared with
drochlorothiazide. In addition to metolazone (45), LD ultrafiltration for fluid removal in heart failure, and
augmentation was demonstrated using chlorothiazide ultrafiltration remains an important modality for refrac-
(13,42), hydrochlorothiazide (43,47), quinethazone (20,21), tory fluid overload (55).
indapamide (48), bendroflumethiazide (21,25), and butizide
(49). Metolazone has been suggested to be superior to other Adverse Effects of CDT
TD in patients with advanced kidney disease (24,50), but
Clinically important adverse effects with CDT are common,
other TD augment the response to LD, even in patients
requiring careful monitoring of serum electrolytes and renal
with advanced renal failure (26,47,49,51). Finally, the as-
function (56). Hypokalemia is particularly frequent and
sertion that a TD should be given at least 30 min before the
reductions in serum potassium from 0.4 to 0.8 mEq/l are
LD was not studied in any article we reviewed (52). Most
common despite aggressive potassium supplementation.
studies reporting benefits of CDT administered the 2 drugs
Potassium-sparing diuretics such as spironolactone can
at the same time. Metolazone has slow and variable absorp-
reduce but do not entirely prevent potassium loss (21,25).
tion in edematous patients, such that the peak effect occurs
Urine potassium loss and resultant hypokalemia tend to
only after several hours (15,45). The benefit of TD (with
correlate with total urine sodium excretion and sodium
their long duration of action) added to LD appears to be
concentration in the final urine. TD produce greater urine
primarily in maintaining diuresis after the shorter-acting
potassium loss per unit of urine sodium excretion than LD,
LD has worn off (49,53).
and CDT is particularly prone to massive urine potassium
excretion, especially with higher baseline LD doses (47). In
Anticipated Benefits of CDT select hospitalized patients prone to hypokalemia, twice-
daily monitoring of potassium levels may be needed, with
Given the baseline differences between the patient popula-
aggressive supplementation of potassium deficits. Hypoka-
tions and the variations in diuretic regimens evaluated, it is
lemia is often associated with hypochloremic (chloride-
difficult to quantify the effects of adding a TD to LD
responsive) metabolic alkalosis because urine chloride losses
therapy. Across studies, mean daily weight loss was variable,
typically exceed urine sodium losses; hypomagnesemia often
with 1 kg per day more typical but as much as 3 to 5 kg over
occurs and can worsen hypokalemia. Hypokalemia, with or
the first 24 h reported (24). Total weight reductions of 5 to
without hypomagnesemia, may increase the risk of cardiac
6 kg over several days in edematous patients were usual, but
arrhythmias, particularly in patients taking digoxin or anti-
weight loss ⬎10 kg was described by several reports
arrhythmic agents. Diuretic-induced electrolyte distur-
(37,42,43) and weight loss ⬎20 kg was rarely reported (24).
bances may contribute to arrhythmic death in heart failure
The response rate to CDT varied based on the patient
patients (57). Hyponatremia can occur because the increase
population, ranging from ⬃70% to 75% in more severely ill
in urine sodium excretion is greater than the increase in
patients (37,43,45) to ⬎90% in many studies. In 1 obser-
urine water excretion with more hypertonic urine after
vational study, lower baseline serum potassium identified
CDT than after LD alone. Hyponatremia appears less
patients less likely to respond to the addition of metolazone
common than hypokalemia and was rarely symptomatic but
to existing LD therapy (45).
can be a marker of adverse heart failure outcomes (58).
Potential benefits of CDT include fluid removal with
Massive diuresis with several liters of urinary fluid loss per
resolution of volume overload and congestion, even in
day has been reported (24), potentially leading to progres-
patients with impaired renal function refractory to LD
sive volume depletion requiring fluid resuscitation (40).
alone. Improved diuresis and relief of fluid overload could
Hypotension can occur, with a mean reduction of 10/8 mm
facilitate earlier hospital discharge and/or prevent rehospi-
Hg in blood pressure recorded in 1 study (45).
talization to reduce the total number of hospital days,
although it has been difficult to correlate weight loss during Renal Function and CDT
heart failure hospitalization with subsequent outcomes (54).
CDT has been associated with improved quality of life in Changes in serum creatinine and creatinine clearance with
some patients with heart failure (41,45). Heart failure CDT may be highly variable. Early short-term controlled
therapies should ideally improve mortality, but CDT may studies did not reveal a significant acute reduction in
not provide such a benefit, considering the powerful neu- creatinine clearance when a TD was added to existing LD
rohormonal activation produced beyond the effect of a LD therapy (21,25); later controlled studies support this con-
alone (13) and lack of proven mortality benefit with LD (6). clusion (33,49). Several studies reported severe, albeit gen-
Metolazone use has been associated with poor outcomes in erally reversible, azotemia developing in patients treated
1532 Jentzer et al. JACC Vol. 56, No. 19, 2010
Combination Diuretic Therapy in Heart Failure November 2, 2010:1527–34

with CDT, particularly in the setting of more advanced Important

Table 4 Considerations Regarding CDT
Important Considerations Regarding CDT
baseline renal dysfunction with higher baseline serum cre-
atinine (59). The rise in blood urea nitrogen was usually ● Addition of thiazide-type diuretics can induce diuresis in patients refractory to
greater than the rise in serum creatinine (26,34,41,45) and massive loop diuretic doses

typically stabilized after 3 to 5 days (51). Increases in serum ● Combination of loop ⫹ thiazide-type diuretics can be effective in patients with
advanced chronic kidney disease
creatinine on the order of 20% to 30% were frequently ● Synergistic effects of thiazide-type diuretics on diuresis appear to be a class
reported. TD alone initially produce a reversible reduction effect seen with all drugs studied
in glomerular filtration rate during peak natriuresis (47), ● Potentially dangerous hypokalemia can develop with CDT, warranting close
which may be attenuated by the addition of LD (53). laboratory monitoring

Chronic TD use is 1 predictor of worsening renal function ● Reversible increases in serum creatinine may be seen but are not the rule;
reductions in creatinine can occur as well
in chronic heart failure patients (60), and the potential for ● Safety and effects on morbidity and mortality with CDT are unknown
worsening renal function is an important concern with
CDT, given the adverse prognosis associated with worsen- CDT ⫽ combination diuretic therapy.

ing renal function in patients with heart failure (61). A

similar to previously published recommendations about use
decrease in serum creatinine can be seen after diuresis with
of metolazone (46). Suggested considerations regarding
CDT, depending on the hemodynamic state of the patient
CDT are summarized in Table 4. CDT is only appropriate
and the pathophysiology of their underlying renal dysfunc-
for patients with gross fluid overload refractory to optimized
tion, potentially by relief of renal venous congestion (62).
doses of intravenous LD, especially in patients with chronic
An initial rise in serum creatinine may be followed by a
decompensated systolic heart failure and impaired renal
sustained fall as diuresis occurs (41). Impaired renal function
function. Adequate doses of LD can be defined as 160 to
with diuretic therapy can result from direct alterations in
320 mg/day intravenous furosemide in divided doses or by
glomerular hemodynamics due to neurohormonal and in-
continuous infusion; this was the usual dose range used in
trarenal feedback mechanisms or from overt volume deple-
studies of CDT. Carefully selected patients with advanced,
tion (63). When excessive diuresis occurs, withdrawal of
refractory, or end-stage (stage D) systolic heart failure may
both diuretics is necessary due to the prolonged half-life of
be candidates for outpatient CDT as a means to prevent
TD, which prolongs further in the presence of significant
recurrent hospitalization for fluid overload, although this
renal insufficiency (46).
approach is not well-studied and requires close follow-up
(2,34,37,50,64). CDT should not be used in patients with
Use of CDT in Clinical Practice
peripheral edema due to local effects such as venous stasis
Leading professional society guidelines all recommend use rather than total-body fluid overload due to a sodium-
of combined LD and TD therapy as 1 of several approaches retaining state. CDT is not an established or recommended
to fluid overload refractory to LD monotherapy, with a approach to hypertension control in the absence of gross
Level of Evidence: C (expert opinion only) (2,50,64). A fluid overload (59). CDT is only expected to be effective in
total of 5 sources were cited in support of this recommen- patients with diuretic resistance due to distal tubule hyper-
dation (12,15,26,41,56), none of which included a placebo- trophy from chronic LD exposure, and other causes of
controlled trial; 1 was a randomized trial without placebo diuretic resistance should be carefully excluded.
control (41). Initiation of CDT should be done with careful observa-
Use of CDT requires weighing the known risks and tion and frequent monitoring of renal function and electro-
potential benefits, summarized in Table 3. Based on the lytes. An equivalent dose of any TD should be effective
available literature, general recommendations can be made (Table 5); longer-acting agents (e.g., metolazone) may be
regarding prudent use of CDT in heart failure patients, more useful for 2 to 3 times weekly dosing. A starting dose

Potential
Table 3 Benefits andBenefits
Potential Adverse and
Effects of CDT
Adverse Effects of CDT Dosing
Table and
5 Duration of Action
Dosing and of TD
Duration of Action of TD

Potential Benefits Potential Adverse Effects Thiazide-Type Equipotent Maximum Daily

Diuretic Dose, mg Dose, mg Duration of Action
Overcoming diuretic resistance Hypokalemia
Bendroflumethiazide* 2.5 20 12–24 h (up to 48 h)†
Relief of fluid overload ⫹ edema Worsening renal function/azotemia
Chlorothiazide 250 1,000 6–12 h (up to 24 h)†
Weight loss Hyponatremia
Chlorthalidone 12.5 100 24–72 h†
Low drug cost Hypochloremic metabolic alkalosis
Hydrochlorothiazide 25 200 6–12 h (up to 24 h)†
Symptomatic improvement Hypotension
Indapamide 2.5 5 36 h
Decrease in systemic congestion Hypovolemia/dehydration
Methylclothiazide 2.5 20 24 h
Diuresis in chronic renal failure Worsening hepatic encephalopathy
Metolazone 2.5 20 12–24 h (up to 48 h)†
Improved ventricular function Cardiac arrhythmias/ectopy
Quinethazone* 25 200 12–24 h†
Hospital discharge Hypomagnesemia
Prevention of readmission Hyperuricemia *Not currently available in the U.S. †Duration of action can prolong substantially in the presence of
renal insufficiency or chronic dosing. Adapted, with permission, from Hunt et al. (2).
CDT ⫽ combination diuretic therapy. TD ⫽ thiazide-type diuretics.
JACC Vol. 56, No. 19, 2010 Jentzer et al. 1533
November 2, 2010:1527–34 Combination Diuretic Therapy in Heart Failure

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