Race Influences the Safety and Efficacy of Spironolactone in Severe Heart Failure
Vardeny et al: Race and Spironolactone in Heart Failure
Orly Vardeny, PharmD, MS; Larisa H. Cavallari, PharmD; Brian Claggett, PhD;
Akshay S. Desai, MD, MPH; Inder Anand, MD; Patrick Rossignol, MD, PhD;
Faiez Zannad, MD, PhD; Bertram Pitt, MD; Scott D. Solomon, MD
for the Randomized Aldactone Evaluation Study (RALES) Investigators
From the University of Wisconsin School of Pharmacy (O.V.), Madison, W
Madison, I; University of
Illinois at Chicago, Chicago, Ill (L.H.C.), Brigham and Women's Hospital, Boston, MA (B.C.,
s Hoospital, Bossto
A.S.D., S.D.S.), University of Minnesota (I.A.), INSERM, Ce
iversity off Minnesota (I.
M C ntre d'Investigations Cliniques-
9501 & INSERM U961, Nancy, France, Université de Lorraine, France (P.R., F.Z.), University
961, Nanccyy, Fraa
of Michigan, Ann Arbor, MI (B.P.)
Orly Vardeny, PharmD, MS
University of Wisconsin School of Pharmacy
777 Highland Avenue
Madison, WI 53705-2222
Email: [email protected]
Journal Subject Codes: Heart failure: Congestive, Treatment: Cardiovascular
Background—The incidence of hyperkalemia due to mineralocorticoid receptor antagonists
(MRAs) may vary by race, but whether race influences efficacy of MRAs in heart failure (HF) is
Methods and Results—We assessed hyperkalemia and outcomes in African Americans (AA,
N=120) and non-African Americans (non-AA N=1543; Caucasian 93%) with NYHA class III or
IV HF and LV dysfunction randomized to spironolactone, titrated to 25mg or 50 mg daily or
placebo in the Randomized Aldactone Evaluation Study (RALES). AA participants were
significantly younger, more likely to have an ischemic HF etiology, more likely to be NYHA FC
IV, have a higher eGFR and heart rate, less hypertension, diabetes, or history of myocardial
infarction compared to non-AA participants. Potassium increased with spironolactone in non-AA
(4.29±0.5 to 4.55±0.49 mmol/L), but not in AA (4.32±0.54 to 4.31±0.49mmol/L; race by
treatment interaction, p=0.03) during the first m
uring the first montthh and re a
m ined higher throughout the trial.
ineed higher thro g
Compared to AA, non-AA were more likely to attain m
m ree likelyy tto atttainn axim
x al spironolactone dose (13.9% vs.
maal sppiironnolactoonne do
5.8%, p = 0.04) and had higher rates of hyperkalem
h gher rates of hyperkale ia (potassium
>5.5 mmol/L, 9.7% vs. 4.2%,
p<0.046), as well as lower rates of hypokalem
lower ratess of hyppokal
p tassiu < 3.5 mmol/L, 5.6% vs. 17.9%, p <
m < 33.55 mmol/L, 55. %
0.001). After adjustment for differences in baseline characteristics and achieved study drug
dose, spironolactone reduced the combined endpoint of death or hospitalization for HF in non-
AA (HR 0.63, 95% CI 0.55-0.73), but not in AA (HR 1.07, 95% CI 0.67-1.71; p-
Conclusions—AA with heart failure exhibited less hyperkalemia and more hypokalemia with
spironolactone compared to non-AA, and appeared to derive less clinical benefit. These
hypothesis-generating findings suggest that safety and efficacy of MRAs may differ by race.
Key Words: heart failure, pharmacology, potassium
Addition of mineralocorticoid receptor antagonists (MRAs) to standard medical therapies
reduces morbidity and mortality in a broad spectrum of patients with heart failure.1-3 Current HF
treatment guidelines recommend the use of MRAs in patients with reduced left ventricular
ejection fraction (LVEF) and moderately severe to severe symptoms of HF, and in patients after
acute myocardial infarction with concomitant symptoms of HF and reduced LVEF.4,5
Hyperkalemia is a known adverse effect from MRAs. Rates of hyperkalemia are higher in
routine clinical practice than previously reported in clinical trials, perhaps due to less stringent
standards for monitoring.6,7 Accordingly, fear of hyperkalemia has led to underuse of this
potentially life-saving therapy.8,9
Previous studies have shown that the incidence of hyperkalem
kale ia in patients treated with
MRAs may vary by race with African Am
ericans exhibiting less hyperkalem
s exxhibiting lesss
ia than non-African
Americans.10,11 Several m
m dical therapies for HF m
y al have differential effects by
so have diffferential eff c
evidenced in post-hoc analyses of the V-HeFT trials,12
y es off thee V-HeFT trials, 2 in which the com
inn whichh thee co b
mbination of hydralazine
and isosorbide dinitrate was more beneficial in African Americans than in the non-African
American population. These findings provided the rationale for the A-HeFT trial, which
demonstrated a 43% reduction in the all-cause mortality with this combination compared to
placebo in the African American population.13 Whether race influences the efficacy of MRAs in
patients with HF, however, is unknown.
We utilized data from the Randomized Aldactone Evaluation Study (RALES) to examine
differences in the incidence of hyperkalemia in African Americans (AA) compared with non-
African Americans (non-AA), and hypothesized that race would modify the efficacy of
spironolactone in patients with HF.
Study Design and Patient Selection
RALES was a double blind, randomized, placebo controlled trial that was designed to assess the
efficacy of spironolactone on prevention of all-cause mortality and cardiac-related
hospitalizations in patients with NYHA Functional Class (FC) III or IV HF. Participants were
enrolled if they had a LVEF < 35% while taking background angiotensin converting enzyme
(ACE) inhibitors and diuretics. Patients with primary valvular disease, congenital heart disease,
unstable angina, liver failure, listing for cardiac transplant, active cancer, or any other life-
threatening disease were excluded as were those with serum creatinine > 2.5 m
atinine > 2.5 g/dL or potassium
> 5 mmol/L. Participants were randomized to receive spironolacton
to e 25mg or placebo daily.
Following 8 weeks, the dose could be increased to
the dose coulld be increas
g daily for participants with signs and
symptoms of progression of HF without evidence of hyperkalem
e iddence off hyperkal
ia (serum potassium
mEq/L). If the participants developed hyperkalem
L). If the participa
p rkalemia at any tim
ia att anyy time, investigators
were given discretion to reduce the dose to 25 mg every other day, but were encouraged to adjust
concomitant medications first. Serum potassium and creatinine were measured at 4, 8, and 12
weeks during the titration phase, and every 3 months thereafter during the study, and were
available in 1658 of the 1663 patients enrolled in the study. Concomitant treatment with digoxin
and vasodilators was allowed, and the use of potassium-sparing diuretics was not permitted. Oral
potassium supplement use was discouraged unless hypokalemia (defined as a serum potassium
concentration of less than 3.5 mmol per liter) developed. The protocol was approved
participating sites' institutional review boards. All participants provided written informed
consent in accordance with established guidelines for the protection of human subjects.
Incidence hyperkalemia was defined as a potassium level 5.5 mmol/L at any visit during study
follow up. Race was self-identified by study participants at the time of enrollment. Baseline
demographics between AA and non-AA participants were compared to identify potential
differences. Between-group assessments were performed using t-tests for continuous variables,
and Chi-Square or Fisher's exact tests, as appropriate, for categorical variables.
We compared potassium levels at baseline and at one month following randomization by
treatment assignment between AA and non-AA participants by un-paired t-tests. In order to test
the hypothesis that the population-averaged relationship between post-baseline potassium
n post baseline p
and treatment was not modified by race, we fit a generalized estimating
g equati s model for
repeated measures, allowing for within-patie
r within-pat nt correlation, and controlling for baseline
potassium value. Cox proportion
ll azards regression m
h zardss reegressiion
odels were used to exam
between treatment assignm
ssign ent and all-cause m
ment and all-cause o
orta ity and the com
y andd the co bined endpoint of death or HF
hospitalization among AA and non-AA. Models were adjusted for the following covariates: age,
sex, diabetes, hypertension, history of MI, NYHA FC, baseline potassium, eGFR, maximal dose
of study medication achieved, and baseline medications (diuretic, ACE inhibitor or ARB, beta-
blocker, digoxin, aspirin). Times to hyperkalemia and hypokalemia between AA and non-AA
were also assessed. Additionally, we performed formal interaction testing between race,
treatment assignment, and the outcomes of hyperkalemia, hypokalemia, all-cause mortality, and
the combined endpoint of death or HF hospitalization. Another model was fit which included
multiple treatment by covariate interaction terms for eGFR, age, gender, NYHA status,
potassium level, and usage of ACE inhibitor/ARB, digoxin, beta-blocker, and loop diuretic at
baseline. Doses of study drug were recorded, and mean and maximal dose achieved were
compared. A critical alpha probability (p) value of <0.05 was considered statistically significant.
All analyses were conducted using Stata, version 11 (StataCorp LP, College Station, TX).
Baseline Patient Demographics
Out of 1663 patients included in the RALES study, 120 (7%) were AA, and 1543 were non-AA
(Caucasian, Asian, or Other). Baseline characteristics by race are shown in the Table. AA
participants were significantly younger, more likely to have an ischemic HF etiology, more
likely to be NYHA FC IV (but similar baseline ejection fraction), have a higher eGF
, have a higheer
rate, less hypertension, diabetes, or history of myocardial infarction compared to non-AA
participants. Moreover, f
, f wer AA participants took beta-blockers and aspirin, and m
digoxin at study entry. More non-A
M re nonn A attained the m
mal dose of study m
f study edication com
to AA participants (13.9% vs. 5.8%, p = 0.04), and m
% vs. 55.8%, p = 00.04), and ean doses of spironolactone were higher in
meann doses off spi
non-AA compared to AA (26.4mg versus 25.1mg, p=0.004). Adherence, assessed by pill counts,
was not different between AA and non-AA participants.
Baseline and Changes in Potassium over Time
Baseline potassium concentrations were comparable between AA and non-AA participants (4.30
± 0.38 mmol/L versus 4.25 ± 0.44 mmol/L, p=0.51). At one month following randomization
(visit 1), potassium levels increased significantly from baseline in non-AA taking spironolactone
(4.30 ± 0.38 vs. 4.55 ± 0.49, p < 0.0001), but not in AAs assigned to spironolactone (4.25 ± 0.4
vs. 4.31 ± 0.49 mmol/L, p = 0.91; between group comparison p<0.001 Figure 1). Potassium
levels at one month post-randomization were similar between AA and non-AA taking placebo
(p=0.97). Mean doses of spironolactone at one month were similar between groups (25.5mg
among AA vs. 26.1mg in non-AA, p=0.45). Differences in potassium concentrations between
AA and non-AA persisted throughout the trial. Controlling for baseline potassium values, study
medication dose (mean and maximum achieved dose), spironolactone was associated with an
overall increase in post-baseline potassium values (mean increase 0.28 mmol/L [p<0.001]). AA
participants experienced a significantly smaller potassium increase associated with treatment
(0.13 vs 0.29 mmol/L for AA vs non-AA, p-interaction = 0.03), and there were no significant
differences between AA and non-AA participants taking placebo (p=0.38).
Rates of hyperkalemia (serum potassium 5.5mmol/L) were higher among non-AA
participants assigned to spironolactone compared to AA participants (16.6% versus 5.4%,
ants (16.6% veers
p<0.001, Figure 2). There were no statistically significant differences in hyperkalem
ences in hyperkka
AA randomized to spironolactone compared to placebo, (5.4
p acceebo, (5.
5 % versus 3.0%, p=0.54). In
comparison, non-AA participants taking spironolact
A participaantts taaki
c one had a statistically higher frequency of
hyperkalemia compared to placebo (16.6% versus 4.8%, p<0.001). Conversely, hypokalem
aredd to placebo (16 6
(serum potassium < 3.5mmol/L) was more frequent among AA participants taking
spironolactone compared to non-AA (19.6% versus 6.1%, p<0.001, Figure 2), and we observed a
significant race by treatment interaction for time to hypokalemia (p-interaction=0.032).
In the placebo group, overall rates of mortality and the combined endpoint of death or HF
hospitalization were similar in AAs and non-AAs (Figure 3). In non-AA participants,
spironolactone was associated with a 30% reduction in the risk for all-cause mortality (adjusted
HR 0.70, 95% CI 0.59, 0.82), and a 36% reduction in the risk for the composite outcome of death
or hospitalization for HF (adjusted HR 0.64, 95% CI 0.55, 0.74) (Figure 4). By contrast, in the
AA participants spironolactone use was associated with no effect on mortality (adjusted HR
0.87, 95% CI 0.47, 1.59), or death or hospitalizations for HF (adjusted HR 1.18, 95% CI 0.72,
1.94) (Figure 4). There was a significant race by treatment interaction for the outcome of death
or hospitalizations for HF (p-interaction=0.032), but not for mortality. Even after adjusting for
multiple treatment by covariate interactions to assess for the effect of baseline covariate
imbalances between AA and non-AA individuals, there remained a significant interaction
between race and treatment on the composite of death or hospitalizations for HF (p-
interaction=0.030). Of note, Blood pressure changes in response to spironolactone at visit 2 and
over the course of the trial were similar between AA and non-AA.
In this analysis of patients with m
h oderately severe to severe HF with reduced ejection f
r too seevere HF
w thh reducced e e
randomized to a mineralocorticoid receptor antagonist or placebo, self-identified AA patients
r ceepttoor antago
r placeboo, self-identi
developed less hyperkalem
rkale ia but higher rates of hypokalem
miaa butt higher rates of hypokal
ia while taking spironolactone
emia while taking
compared to similarly treated non-AA patients. Despite a similar initial study drug dose,
potassium concentrations increased substantially in non-AA individuals assigned to
spironolactone within a month following randomization, while potassium levels in AA
participants did not change significantly. However, AA participants appeared to derive less
clinical benefit from an MRA.
Differences in potassium response to spironolactone among AA and non-AA participants
were evident early in the study and persisted throughout the trial. Non-AA participant potassium
levels increased, on average, by 0.25mmol/L while taking spironolactone compared to those
taking placebo. Changes in potassium concentrations were minimal in AA participants. In
addition, there were lower rates of hyperkalemia and higher rates of hypokalemia among AA.
Our findings are consistent with two other analyses that also reported less pronounced changes in
serum potassium in AA patients with HF taking spironolactone compared to non-AA.10,11
Patients with heart failure may be at higher risk for hyperkalemia from renin-angiotensin-
aldosterone system blockers, due to inherently diminished renal perfusion, reducing delivery of
sodium at distal tubule sites, which results in decreased potassium excretion.14 Several risk
factors are known to further augment the risk for hyperkalemia in those with heart failure,
including renal dysfunction, diabetes, and use of concomitant medications that enhance
potassium levels such as ACE inhibitors or ARBs and beta adrenergic blockers.15 In the RALES
study, AA participants had higher calculated eGFRs and less diabetes, in addition to a lower
betes, in additiion
frequency of beta blocker use, and lower mean doses of study medication. These differences in
the two groups may have
haav contributed to different rates of hyperkalem
to different traattes of hyperrkale ia and hypokalem
observed between them
m Wee atttee pted to control
d to conntrol for baselin
forr baseli e differences between groups in our
analyses. In addition, there was a statistically significant, but num
nn, there was a statistically
y significant, butt nu erically sm
l mean difference
of 1.3 mg) difference in spironolactone dose between groups. This small dose difference would
not be expected to result in the profound potassium differences observed, but the fact that less
AA achieved maximum dose of spironolactone could have also impacted potassium levels.
We found that spironolactone was less effective in reducing death or HF hospitalization
in AAs than in non-AA. There are no prior randomized data analyzing the effect of
spironolactone on clinical outcomes by race, and most large randomized trials with MRAs have
too few AAs to elucidate outcomes by self-reported race. In an post hoc analysis of A-HeFT
study, in which AA patients were randomized to a fixed dose combination of hydralazine and
isosorbide dinitrate (FDC-H/I) or placebo in addition to standard therapy, spironolactone use was
not associated with a reduction in all-cause mortality, mortality or first HF hospitalization, or
first HF hospitalization in the overall sample.16 However, when the analysis was done within
each randomized treatment group, spironolactone use was associated with a 59% reduction in all-
cause mortality in the FDC-H/I group but not in the placebo group, suggesting a synergistic
effect of the MRA with FDC-H/I. Although 39% of A-HeFT study participants were taking
spironolactone, this treatment was not randomized, thus, these observations may be confounded.
The mechanisms underlying differences by race in potassium and clinical responses to
spironolactone are unclear, but several mechanisms have been postulated. First, adherence has
previously been shown to be lower among AA patients in general17,18 and reduced adherence
may negatively affect outcomes,19 although adherence as assessed by pill count was not different
d by pill count w
by race in the RALES study. Moreover, the minimal difference in dose of
n doosee o spironolactone
between the two groups is unlikely to explain these differences in outcom
ouupps is unnliike
ain these differences in outcom
patients respond less favorably to neurohorm
monal inhibition com
ll innhhibition c
om ared to non-AA is
controversial. A post-hoc analysis of the SOLVD (Studies on Left Ventricular Dysfunction
y is off thee SOLVD
( tudies onn Leftt Ventricular D
demonstrated less blood pressure lowering with enalapril in AA compared to non-AA, and
higher rates of hospitalizations.20 In the ALLHAT study, AA exhibited higher relative risk for
incident coronary heart disease, stroke, and heart failure while taking lisinopril compared to non-
AA, however formal testing for race and treatment interaction in predicting HF was not
significant.21 With beta adrenergic receptor blockers, one analysis found an attenuated effect on
death or hospitalization among AA with heart failure,22 while other analyses suggested similar
benefits between AA and non-AA.23,24 Discrepancies in study findings may be related to unclear
environmental or genetic contributors, or to instability in point estimates of efficacy related to
small numbers of AA patients enrolled in the large scale clinical trials.
Mineralocorticoid receptor antagonists (MRAs) lead to increased serum potassium
concentrations by interfering with aldosterone's activity at the mineralocorticoid receptor, thus
reducing renal excretion of potassium via the Na+/K+-ATPase.25 Mineralocorticoid receptors are
also present in cardiac tissue, where they are believed to modulate cardiac responses, such as
anti-fibrotic effects, to MRAs.26 Differences in the mineralocorticoid receptor, also referred to as
the nuclear receptor superfamily 3, group C, member 2 (NR3C2), could potentially contribute to
racial differences in MRA response. For example, a single nucleotide polymorphism located in
the NR3C2 gene, c.-2C>G (rs2070951), occurs more commonly in Caucasians compared to AAs
(prevalence of 45% versus 20-30%) and results in altered receptor activity.27
or activity. More pronounced
potassium elevations in response to spironolactone have been reported among
carriers.28 It is possibl
bble that clinical outcom
e may also be associated with genetic variants of the
might vary by race. W
r NR3C genotype also impacts
clinical outcomes with
i MRAs and contributes to racial differences in MR
th MRAss andd contributes to raciall differencess in M A response is unknown
and unfortunately cannot be evaluated in RALES because genetic samples are not available.
Finally, a potassium-sparing effect defined by a serum potassium increase of 0.11
mmol/L after one month independently contributed to the mortality and morbidity benefit of
eplerenone in HF patients post myocardial infarction in EPHESUS (Eplerenone Post-Acute
Myocardial Infarction Heart Failure Efficacy and Survival study).29 This small serum potassium
elevation associated with a MRA was consistent with that reported in a review of the use of
RAAS inhibitors in a broad spectrum of clinical studies.30 Although hyperkalemia is generally
the aspect of potassium homeostasis that is discussed in the context of MRAs, hypokalemia is
also clinically important. Some data suggest that hypokalemia in patients with HF may be
associated with increased mortality.31-33 In the present study, it was shown that AA exhibited
lower serum potassium concentrations while taking spironolactone and more frequent
hypokalemia. Altogether, it may therefore also be proposed that the lower serum potassium
levels observed in AA compared to non AA participants may have contributed to the poorer
Some limitations of this study should be noted. This was a post-hoc analysis of the
RALES study and hence the results should be interpreted with caution. In particular, the number
of AA was small therefore point estimates noted are not definitive. However, serum potassium
results are consistent with those from previous analyses. Beta blocker usage in the RALES study
was low, and beta blockers are known to reduce mortality in HF and also enhance the risk for
hyperkalemia. As such, it is unclear whether the magnitude of differences observed in
hyperkalemia rates, or in rates of m
s of ortality or death and hospitalization from HF, would be
similarly observed with contem
porary HF therapy. Baseline characteristics of AA in the RALES
r HF thherapyy. Baseline
a teristics of AA
study differed from those of AA enrolled in A-HeFT study, including base
A enrolled inn A-HeFT studyy, including ba line renal function and
higher incidence of ischemic etiology. As such, results from these analyses cannot be
extrapolated to all AA. Furthermore, our findings are in the setting of low dose spironolactone
and we cannot exclude the possibility that higher spironolactone doses may confer enhanced
clinical benefits and negate any differences by race. We believe this question requires further
investigation. The differential effect of spironolactone on changes in potassium by race appeared
to be concordant with the effect of spironolactone on outcomes. However, we cannot determine
whether potassium changes simply represent a marker of response to spironolactone or whether
these changes may have played a role in the differential outcomes observed. Lastly, we cannot
exclude the possibility that drug interactions occurred as a result of differences in unidentified
medication use between AA and non-AA, and it is possible that these drug interactions could
have affected the efficacy of spironolactone.
In summary, we found that among patients with advanced HF, those of African American
heritage exhibited lower serum potassium levels with spironolactone compared to non-African
Americans, and appeared to derive less clinical benefit. While limited by a small number of
African American participants and power, these hypothesis generating findings raise the
possibility that safety and efficacy of MRAs may differ by heritage, and suggests the need for
further prospective investigation.
Sources of Funding
The RALES Trial was funded by Searle (Skokie,
was funded by Searle
i , Ill). No additional funding was provided for
Skokie, Illl)). No additional funding wa
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Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. The New England journal of medicine. 2003;348:1309-1321.
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Table. Baseline Characteristics by Race
120.0 ± 20.9 / 76.9 ± 12.3
122.4 ± 20.0/74.4 ± 11.5
Figure 1. Potassium levels (mmol/L) during the study by treatment and race. AA = African
American, non-AA = non-African American, PL = placebo.
Figure 2. Percentage of Patients experiencing any hypokalemic (K < 3.5) or Hyperkalemic (K >
5.5) event during follow-up, by race and treatment group. African Americans demonstrated less
hyperkalemia among those randomized to spironolactone (black bars), but more hypokalemia on
spironolactone compared to non-African Americans (race x treatment p-interaction = 0.032 for tim
nt p interactioonn
to hypokalemia). * indicates p<0.001 for comparisons between African Am
erican and non-African
Figure 3. Kaplan-Meier curves show
r curves sho ing sim
lacebo e ent rates for all-cause m
vent rates for all-cause o
m rtality (Panel
A) and the composite of death or hospitalization for HF (Panel B) in non-African Americans (black
line) and African Americans (dashed) in the RALES study.
Figure 4. Kaplan-Meier curves showing all-cause mortality (top panel) and death or hospitalization
for HF (bottom panel) for participants in the spironolactone group (black) and placebo group
(dashed) among non-African Americans (left panel) and African Americans (right panel). The
combined endpoint of death or hospitalization for HF were reduced in non-AA Americans
randomized to spironolactone, but not in AA participants taking spironolactone (death or HF
hospitalization), adjusted p-interaction = 0.034.
Potassium (mEq/L) 4.1
Percent of Patients (%) 5
Hospitalization for HF
Days post Randomization
Days post Randomization
Days post Randomization
Days post Randomization
Death or Hospitalizations for HF, Non-AA
Death or Hospitalizations for HF, AA
Days post Randomization
Days post Randomization
Race Influences the Safety and Efficacy of Spironolactone in Severe Heart Failure
Orly Vardeny, Larisa H. Cavallari, Brian Claggett, Akshay S. Desai, Inder Anand, Patrick Rossignol,
Faiez Zannad, Bertram Pitt and Scott D. Solomon
Circ Heart Fail. published online August 12, 2013;
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Copyright 2013 American Heart Association, Inc. All rights reserved.
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