Influence of Age on Efficacy and Safety of Spironolactone in Heart Failure

JACC: HEART FAILURE

VOL. 7, NO. 12, 2019

PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

Influence of Age on Efficacy and Safety of Spironolactone in Heart Failure Orly Vardeny, PHARMD, MS,a,b Brian Claggett, PHD,c Muthiah Vaduganathan, MD, MPH,c Iris Beldhuis, BSC,c Jean Rouleau, MD,d,e Eileen O’Meara, MD,d,e Inder S. Anand, MD,a,b Sanjiv J. Shah, MD,f Nancy K. Sweitzer, MD,g James C. Fang, MD,h Akshay S. Desai, MD,c Eldrin F. Lewis, MD, MPH,c Bertram Pitt, MD,i Marc A. Pfeffer, MD,c Scott D. Solomon, MD,c on behalf of the TOPCAT Investigators

ABSTRACT OBJECTIVES The authors examined efficacy and safety of spironolactone by age in the Americas region (N ¼ 1,767) of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. BACKGROUND Heart failure with preserved ejection fraction disproportionately affects older adults who may exhibit changes in physiology and variable pharmacokinetics. METHODS TOPCAT enrolled patients with heart failure and a left ventricular ejection fraction $45% who were age 50 or older with an estimated glomerular filtration rate $30 mL/min/1.73 m2 and prior heart failure hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo with a mean follow-up duration of 3.3 years. We assessed treatment effect and safety by protocol-defined age categories (<65, 65 to 74, and $75 years). RESULTS The mean age was 72  10 years (range 50 to 97 years) with 41% over the age of 75 years. Participants $75 years were more commonly women and white and had a lower body mass index and estimated glomerular filtration rate compared with the younger age categories. Spironolactone reduced the primary composite outcome compared with placebo across all age categories (p interaction ¼ 0.42). However, spironolactone was associated with an increased risk of the safety endpoint (hazard ratio: 2.54; 95% confidence interval: 1.91 to 3.37; p < 0.001), particularly in older age groups (p interaction ¼ 0.02). Findings in the whole TOPCAT cohort were consistent with results from the Americas region. CONCLUSIONS In this post hoc, exploratory analysis of the TOPCAT trial data from the Americas region, although there was no effect of age on efficacy, there were considerable effects of age on increased rates of adverse safety outcomes. These results should be weighed when considering spironolactone for older heart failure with preserved ejection fraction patients. (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist [TOPCAT]; NCT00094302) (J Am Coll Cardiol HF 2019;7:1022–8) Published by Elsevier on behalf of the American College of Cardiology Foundation.

From the aMinneapolis VA Medical Center, Minneapolis, Minnesota; bUniversity of Minnesota, Minneapolis, Minnesota; cBrigham and Women’s Hospital, Boston, Massachusetts; dInstitut de Cardiologie de Montreal, Montreal, Quebec, Canada; eUniversité de Montreal, Montreal, Quebec; fNorthwestern University Feinberg School of Medicine, Chicago, Illinois; gUniversity of Arizona, Tucson, Arizona; hUniversity of Utah, Salt Lake City, Utah; and the iUniversity of Michigan, Ann Arbor, Michigan. The TOPCAT study was supported by a contract from the National Heart, Lung, and Blood Institute, National Institutes of Health (HHSN268200425207C). The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the U.S. Department of Health and Human Services. Dr. Vardeny has received research grants from AstraZeneca; and has consulted for Novartis, Amgen, and SanofiPasteur. Dr. Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (National Institutes of Health [NIH]/NCATS Award UL 1TR002541); and serves on advisory boards for Amgen, AstraZeneca, Bayer AG, and Baxter Healthcare. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, and Novartis; and has served as a consultant/advisory board/steering committee member for Abbott, Actelion, AstraZeneca, Amgen, Bayer, BoehringerIngelheim, Cardiora, Coridea, CVRx, Eisai, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Tenax, and United Therapeutics. Dr. Rouleau has consulted for Novartis and AstraZeneca. Dr. Fang has served on steering committees for Novartis, Amgen, AstraZeneca, and J & J. Dr. Lewis has received institutional research grants from Novartis, Amgen, and Sanofi in order to conduct clinical trials; and has received consulting fees from Novartis. Dr. Pitt has received consulting fees from Amorcyte, AstraZeneca, Aurasense, Bayer, BG Medicine, Gambro, Johnson & Johnson, Mesoblast, Novartis, Pfizer, Relypsa, and Takeda; research grant support from Forest Laboratories; holds stock in Aurasense, Relypsa, BG Medicine, and Aurasense; and has a pending

ISSN 2213-1779/$36.00

https://doi.org/10.1016/j.jchf.2019.08.019

Vardeny et al.

JACC: HEART FAILURE VOL. 7, NO. 12, 2019 DECEMBER 2019:1022–8

H

eart failure (HF) is the leading cause of

METHODS

ABBREVIATIONS AND ACRONYMS

morbidity and mortality in older adults and results in worse outcomes among these

PATIENTS. The detailed design and primary

patients compared with younger individuals with HF

results of the TOPCAT trial have been previ-

(1). Despite this, older adults are under-represented

ously published (7,10). Briefly, TOPCAT was

in clinical trials of HF therapies (2). Altered physi-

an international, prospective, randomized,

ology,

polypharmacy,

double-blind, placebo-controlled trial of spi-

and comorbid conditions may all affect drug efficacy

ronolactone in patients with HFpEF. The

and safety in response to HF drug treatment among

study enrolled 3,445 individuals age 50 or

older individuals (3). Moreover, HF with preserved

older with at least 1 symptom and 1 sign of

reduced ejection fraction

ejection fraction (HFpEF) is a condition that dispro-

chronic HF, a left ventricular ejection fraction

HR = hazard ratio

portionately affects older adults (4) and for which

of 45% or higher, controlled systolic blood

few treatments have been demonstrated to improve

pressure, and a serum potassium level <5.0 mmol/l.

clinical outcomes.

Additional eligibility criteria included either hospi-

variable

pharmacokinetics,

CI = confidence interval eGFR = estimated glomerular filtration rate

HF = heart failure HFpEF = heart failure with preserved ejection fraction

HFrEF = heart failure with

talization within the previous 12 months for the

SEE PAGE 1029

management of HF or elevated natriuretic peptide (MRAs)

levels (B-type natriuretic peptide $100 pg/ml or N-

consistently reduce morbidity and mortality in pa-

terminal pro–B-type natriuretic peptide $360 pg/ml)

tients with HF with reduced ejection fraction (HFrEF)

within 60 days of randomization. Key exclusion

across the full spectrum of disease severity, but data

criteria included severe systemic illness portending a

in

from

reduced life expectancy of <3 years, advanced

patients enrolled in the Americas region from the

chronic kidney disease (defined as an estimated

TOPCAT (Treatment of Preserved Cardiac Function

glomerular filtration rate [eGFR] <30 ml/min/1.73 m 2

Heart Failure with an Aldosterone Antagonist) trial of

of body surface area or serum creatinine of 2.5 mg/dl

patients with HFpEF were strongly suggestive of re-

or higher). The mean study follow-up was 3.3 years.

ductions in cardiovascular death and HF hospitaliza-

The protocol was approved at each participating site

tion in patients enrolled in the Americas with event

by an ethics committee or institutional review board.

rates typical of an HF population (5–7). As such, MRAs

All participants provided written informed consent in

are recommended by the American College of Cardi-

accordance with established guidelines for the pro-

ology/American Heart Association/Heart Failure So-

tection of human subjects.

Mineralocorticoid

HFpEF

are

1023

Spironolactone in Older Adults With HFpEF

receptor

more

antagonists

limited.

Data

ciety of America HF treatment guidelines for select

Participants were randomized to receive spi-

patients with HFrEF (Class Ia) and HFpEF (Class IIb)

ronolactone 15 mg daily or placebo, which could be

who do not have contraindications to their use (8).

increased every 4 weeks over a period of 4 months up

Nevertheless, the use of MRAs in clinical practice has

to 45 mg daily. Potassium and serum creatinine were

been low, in part because of concerns for hyper-

measured at baseline, within a week of medication

kalemia and worsening renal function (9). Given the

dose changes, and at each study visit. If potassium

potential for divergent drug efficacy and safety of

levels were $5.5 mmol/l, investigators were advised

MRAs and limited clinical trial data in older patients

to reduce the study medication dose by 1 level and

with HF, we sought to examine efficacy and safety of

recheck laboratory values 1 week later. If the partici-

spironolactone by age in the Americas subset of the

pant was already taking the lowest dose of study

TOPCAT trial.

medication, if the potassium level was $6.0 mmol/l,

patent related to site-specific delivery of eplerenone to the myocardium. Dr. Pfeffer has received research support from Novartis; serves as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Novo Nordisk, Sanofi, Teva, and Thrasos; and has stock options in DalCor. Dr. Desai has received consulting fees from Novartis, AstraZeneca, Abbott, Relypsa, and DalCor Pharma; and research grants from Novartis. Dr. Sweitzer has received research grants from Merck and Novartis; and consults for Myokardia and Acorda. Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/National Heart, Lung, and Blood Institute (NHLBI), Novartis, Sanofi Pasteur, Theracos; and has consulted for Akros, Alnylam, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 3, 2019; revised manuscript received August 26, 2019, accepted August 26, 2019.

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Vardeny et al.

JACC: HEART FAILURE VOL. 7, NO. 12, 2019 DECEMBER 2019:1022–8

Spironolactone in Older Adults With HFpEF

a secondary safety endpoint was examined, which

T A B L E 1 Baseline Characteristics by Age Category

included the components of the primary safety

Age <65 Years (n ¼ 492)

Age 65–74 Years (n ¼ 555)

Age $75 Years (n ¼ 720)

59  4

70  3

81  4

Age, yrs

p Value

endpoint in addition to noncardiovascular death to account for competing risk. Other safety endpoints examined included doubling of serum creatinine

Women

229 (46.5)

266 (47.9)

387 (53.8)

0.025

White race

329 (66.9)

438 (78.9)

617 (85.7)

0.001

(defined as $2 times the baseline level and above the

0.08

upper reference limit), hyperkalemia defined as a

NYHA functional class I

29 (5.9)

36 (6.5)

34 (4.7)

II

282 (57.7)

349 (63.0)

412 (57.3)

III

173 (35.4)

167 (30.1)

270 (37.6)

IV

5 (1.0)

2 (0.4)

3 (0.4)

281 (57)

276 (50)

231 (32)

Diabetes mellitus

sampled potassium >5.5 mmol/l, and a serious adverse event related to hypotension. STATISTICAL

ANALYSIS. The

study sample was

0.001

divided into 3 groups based on age at study baseline

Smoking

68 (14)

32 (6)

17 (2)

<0.001

as follows: age <65 years, 65 to 74 years, and 75 years

Atrial fibrillation

118 (24)

251 (45)

374 (52)

<0.001

or older. These age subgroups were predefined by the

Peripheral artery disease

47 (10)

72 (13)

88 (12)

0.20

TOPCAT study protocol. Age was also examined as a

History of stroke

37 (8)

52 (9)

69 (10)

0.43

History of PCI

94 (19)

115 (21)

135 (19)

0.65

continuous variable, in addition to categorically as

ACE inhibitor

293 (60)

273 (49)

325 (45)

<0.001

Angiotensin receptor blocker

148 (30)

185 (33)

218 (30)

0.41

characteristics were compared between categorical

Aspirin

319 (65)

321 (58)

387 (54)

<0.001

age groups with regression for continuous variables

Diuretics

435 (89)

499 (90)

639 (89)

0.68

and the chi-square test for trends for categorical

History of HF hospitalization

341 (70)

346 (63)

353 (49)

<0.001

variables. Event rates adjusted for baseline charac-

History of myocardial infarction

90 (18)

121 (22)

148 (21)

0.37

teristics

Systolic blood pressure, mm Hg

128  17

128  16

127  16

0.86

Heart rate, beats/min

71  12

69  11

68  11

< 0.001

included age, sex, race, New York Heart Association

Body mass index, kg/m2

38  10

34  7

31  6

<0.001 <0.001

70  22

61  18

54  16

4.2  0.4

4.2  0.5

4.2  0.4

Estimated GFR Baseline potassium

0.039

age $65 years of age versus <65 years. Baseline

were

calculated.

Adjustment

variables

functional class, smoking, history of diabetes mellitus, atrial fibrillation, peripheral artery disease, myocardial infarction, stroke, percutaneous intervention, prior HF hospitalization, baseline use of

Values are mean  SD or n (%).

angiotensin-converting enzyme inhibitors or angio-

ACE ¼ angiotensin-converting enzyme; HF ¼ heart failure; GFR ¼ glomerular filtration rate; NYHA ¼ New York Heart Association; PCI ¼ percutaneous intervention.

tensin receptor blockers, aspirin, diuretics, baseline systolic blood pressure, heart rate, body mass index,

or if serum creatinine was $3.0 mg/dl, the study medication was discontinued. At the investigator’s discretion, study medication could be reinitiated upon improvement of potassium levels and/or renal function. Because of regional differences in partici-

eGFR, QRS duration, and baseline potassium levels. Cox proportional hazards analyses were used to assess treatment effects on safety and efficacy and testing for interactions by age category.

RESULTS

pant demographics, outcomes, and responses to spironolactone that raised questions of trial conduct in

The mean age of the overall cohort (N ¼ 1,767) was

Russia and the Republic of Georgia (11), data for this

71.5  9.7 years (range 50 to 97 years). There were 492

exploratory, post hoc analysis were restricted to partic-

participants under age 65 years of age (28%, mean age

ipants enrolled in the Americas region (United States,

59  4 years), 555 participants between ages 65 and 74

Canada, Argentina, and Brazil; N ¼ 1,767), and we have

(31%, mean age 70  3 years), and 720 participants age

provided data from an analysis of the full trial cohort.

75 or older (41%, mean age 81  4 years). Individuals

OUTCOMES. The primary efficacy endpoint for this

in the oldest age category were more commonly

analysis was a primary study composite of cardiovas-

women and white, had lower body mass index and

cular death, aborted cardiac arrest, and hospitaliza-

eGFR compared with younger age categories, and

tion

included

greater QRS duration (Table 1). Older participants had

cardiovascular death, all-cause death, and hospitali-

more atrial fibrillation, but fewer had been previously

zation for HF. The primary safety outcome was

hospitalized for HF or used angiotensin-converting

discontinuation of study medication due to an adverse

enzyme inhibitors at baseline.

event of interest, including hyperkalemia (defined as

CLINICAL OUTCOMES BY AGE AND EFFICACY OF

potassium level $ 5.5 mmol/l), worsening renal func-

SPIRONOLACTONE. After

tion (rise in serum creatinine to $ 3.0 mg/dl),

factors, the risks for the primary outcome and for

gynecomastia, or intolerance. As a sensitivity analysis,

all-cause mortality were greater for individuals in the

for

HF.

Secondary

endpoints

adjustment for clinical

Vardeny et al.

JACC: HEART FAILURE VOL. 7, NO. 12, 2019 DECEMBER 2019:1022–8

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Spironolactone in Older Adults With HFpEF

C ENTR AL I LL U STRA T I O N Efficacy and Safety of Spironolactone Versus Placebo by Age Group

Treatment Effect on Primary Endpoint by Age

Treatment Effect on Safety Outcome by Age

Favors Favors Spiro Placebo

Favors Spiro

Favors Placebo

Overall Interaction P = 0.42

Interaction P = 0.02

Age category (yrs) <65 N = 492

65 - 74 N = 555

≥75 N = 720

.5 1 1.5 2 Hazard Ratio for Efficacy

.5 1 1.5 2 2.5 3.5 5 6 7 Hazard Ratio for Safety

Vardeny, O. et al. J Am Coll Cardiol HF. 2019;7(12):1022–8.

Treatment efficacy and safety by age group in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study. Spironolactone reduced the incidence of the primary outcome relative to placebo consistently across age categories (p interaction ¼ 0.42). The primary safety endpoint occurred more frequently in those randomized to spironolactone, which was more evident among those in the older age categories (p interaction ¼ 0.02).

oldest age category compared with those younger

and was consistently effective across all age cate-

than age 65 years. Spironolactone reduced the inci-

gories (p interaction ¼ 0.42, Central Illustration,

dence of the primary outcome relative to placebo for

Table 2). Likewise, there was no significant interac-

the population as a whole (hazard ratio [HR]: 0.82;

tion between treatment and age for the endpoints of

95% confidence interval [CI]: 0.69 to 0.98; p ¼ 0.03)

HF hospitalization, cardiovascular death, or all-cause

T A B L E 2 Adjusted Incidence Rates and Hazard Ratios for Efficacy and Safety by Age Category

Age <65 Years (n ¼ 492) Adjusted Incidence Rate (per 100 Patient-Years) Outcome

PL

SP

12.1

8.7

All-cause mortality

4.4

Primary composite safety outcome†

4.5

Primary composite outcome*

HR (95% CI) p Value

Age $75 Years (n ¼ 720)

Age 65–74 Years (n ¼ 555) Adjusted Incidence Rate (per 100 Patient-Years) PL

SP

0.68 (0.48–0.97) 0.036

13.6

12.7

4.4

0.89 (0.54–1.60) 0.66

8.1

6.9

1.30 (0.74–2.20) 0.38

3.2

HR (95% CI) p Value

Adjusted Incidence Rate (per 100 Patient-Years)

HR (95% CI) p Value

p Interaction

PL

SP

0.92 (0.60–1.30) 0.61

15.3

14.5

0.84 (0.64–1.10) 0.2

0.42

6.0

0.74 (0.50–1.10) 0.12

10.1

9.0

0.90 (0.68–1.20) 0.45

0.62

9.6

3.60 (2.10–6.40) <0.001

6.2

13.5

3.40 (2.10–5.30) <0.001

0.02

*Composite of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. †Discontinuation of study medication due to an adverse effect, which included hyperkalemia (defined as potassium level $5.5 mmol/l), rise in serum creatinine to $3.0 mg/dl, gynecomastia, or intolerance. CI ¼ confidence interval; HR ¼ hazard ratio; PL ¼ placebo; SP ¼ spironolactone.

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JACC: HEART FAILURE VOL. 7, NO. 12, 2019 DECEMBER 2019:1022–8

Spironolactone in Older Adults With HFpEF

mortality (all p interaction >0.15). Results were

through 3 years of follow-up in the group receiving

similar when age was modeled as a continuous vari-

spironolactone (1.8 mg per category; p ¼ 0.001) but

able (data not shown).

not in the group receiving placebo.

SAFETY OUTCOMES. The composite safety endpoint

In a sensitivity analysis that included results from

of permanent study medication discontinuation due

the entire TOPCAT cohort, findings were consistent

to hyperkalemia, worsening renal function, gyneco-

with the analyses from the Americas region (Online

mastia, or medication intolerance in the placebo

Table 3). The effect of spironolactone on the pri-

group was similar in the <65 and 65 to 74 age cate-

mary efficacy endpoint compared with placebo was

gories and numerically highest in the oldest partici-

consistent across age categories (p interaction ¼ 0.50)

pants (p trend ¼ 0.09). Occurrence of the composite

(Online Table 4). The primary safety endpoint

safety endpoint was more frequent in those ran-

occurred more frequently with spironolactone among

domized to spironolactone compared with placebo

individuals in the older age categories, although the

(HR: 2.54; 95% CI: 1.91 to 3.37; p < 0.001), and the

interaction with age was not statistically significant

relative increase was greatest in older individuals

(Online Figure 1). The safety results were primarily

(p interaction ¼ 0.02) (Table 2). These results were

driven by higher rates of hyperkalemia in older par-

primarily driven by discontinuation for hyperkalemia

ticipants, which was consistent with findings from

or for worsening renal function; the number of

the Americas region (Online Table 5).

discontinuation events for gynecomastia or intolerance was low (Online Table 1). Findings were qualita-

DISCUSSION

tively similar when age was modeled as a continuous variable; however, the interaction p value was short of

In patients with HFpEF enrolled from the Americas in

statistical significance (p interaction ¼ 0.07).

the TOPCAT study, the benefit of spironolactone

The secondary safety endpoint, composed of the

relative to placebo on reducing the composite of

composite of the primary safety endpoint and non-

cardiovascular death, aborted cardiac arrest, and

cardiovascular death, was also more frequent among

hospitalization for HF was independent of age.

participants randomized to spironolactone, with

However, discontinuation due to the development of

higher risk in the older age categories (Online

the composite of hyperkalemia, worsening renal func-

Table 2). Likewise, the risk for hyperkalemia from

tion, gynecomastia, or intolerance was more frequent in

spironolactone relative to placebo was higher in the

those randomized to spironolactone, and older in-

65- to 74-year age category compared with those

dividuals were more likely to discontinue spironolactone

younger than age 65 years (age <65 years: HR: 1.75;

compared with those younger than age 65 years.

95% CI: 1.09 to 2.90; age 65 to 74 years: HR: 6.45;

MRAs are known to reduce morbidity and mortality

95% CI: 3.7 to 11.2; p interaction ¼ 0.01). However, the

in patients with HFrEF and are recommended by HF

risk among those older than 75 was lower than the

treatment guidelines for use in appropriately selected

risk for ages 65 to 74 years; thus, the overall interac-

patients without an age cutoff (8,12). However, MRAs

tion for hyperkalemia from spironolactone by the 3

are underused in clinical practice, especially among

age

significant

older adults, due to concerns for renal function

(age $75 years: HR: 2.9; 95% CI: 1.0 to 4.1; p

deterioration, hyperkalemia, and potential intoler-

interaction ¼ 0.41; Online Table 2). Similarly, we

ance related to multiple comorbidities, frailty, and

did not observe a significant treatment interaction

concomitant drug therapy (9). Post hoc analyses of

with

creatinine

MRA trials have shown that even in patients with

(p interaction ¼ 0.71) or serious adverse event due to

baseline renal dysfunction or those who experience

hypotension (p interaction ¼ 0.55). The number

worsening renal function, outcomes are favorable

needed to harm to observe 1 composite safety event

with an MRA compared with placebo (13,14), and

with spironolactone in participants under age 65

among patients who experience moderate hyper-

years was 31, and among those age 65 years or older, it

kalemia, the benefit of spironolactone is maintained

categories

age

for

was

not

doubling

statistically

of

serum

was 6. We observed a significant interaction between

(15). However, clinical trials supporting the efficacy of

age and treatment with respect to total study medi-

MRAs in HFrEF enrolled participants with a mean age

cation discontinuation (for any reason), such that

of 64 to 68 years, and less than one-third were over

older patients were more likely to discontinue spi-

age 75 years. Because older patients may be at higher

ronolactone compared with younger individuals

risk for adverse outcomes associated with MRAs, it is

but

placebo

important to understand whether the benefit of this

(p interaction ¼ 0.02). The dose of study drug was

class of drugs lessens with age, which could result in

lower with increasing age category at all visits

an altered risk/benefit profile.

not

more

likely

to

discontinue

Vardeny et al.

JACC: HEART FAILURE VOL. 7, NO. 12, 2019 DECEMBER 2019:1022–8

Spironolactone in Older Adults With HFpEF

We observed no heterogeneity of spironolactone’s

treatment with spironolactone, which should be

treatment effect on the primary outcome by age in the

individualized based on patient-specific risk profiles

TOPCAT study, suggesting that older adults may still

and involve shared decision making with patients and

derive similar benefit to that observed in younger

families.

individuals. There are limited prior analyses exam-

Consistent with the 2017 American College of Car-

ining the effect of age on MRA benefit. A systematic

diology Expert Consensus Decision Pathway on HF,

review that assessed results from MRA clinical trials

these data emphasize that at a minimum the imple-

did not identify a treatment interaction with age on

mentation of spironolactone in selected patients with

trial primary endpoints for HFrEF studies (16),

HFpEF in clinical practice should mirror practices in

although in the EMPHASIS-HF (Eplerenone in Mild

TOPCAT with judicious follow-up and monitoring,

Patients

in

especially among older adults, with the realization

Heart Failure) trial, the benefit of eplerenone was

that even within a closely monitored clinical trial,

driven primarily by a reduction of HF hospitalizations

adverse effects were notably higher among older pa-

and not cardiovascular mortality in patients $75

tients; thus, adverse events in a real-world setting

years of age (5). In HFpEF, TOPCAT represents the

may be substantially higher in patients with multiple

only outcome data to address this issue, although an

comorbidities who were likely excluded from the

ongoing registry-based prospective randomized clin-

TOPCAT trial (19). It is unknown whether more

ical study with spironolactone in HFpEF may provide

stringent laboratory monitoring than was performed

additional insight (17).

in the TOPCAT trial would have prevented adverse

Hospitalization

and

Survival

Study

We observed more permanent study medication

events and study medication discontinuation.

discontinuations for hyperkalemia, worsening renal

STUDY LIMITATIONS. We limited this post hoc anal-

function, gynecomastia, or intolerance among par-

ysis to patients from the Americas region only

ticipants over age 65 years compared with younger

because of concerns for study conduct at sites located

individuals. A previous study that examined the use

in Russia and the Republic of Georgia, thus reducing

of eplerenone among older adults discharged post–

the overall sample size. As a sensitivity analysis, we

myocardial

2-fold

replicated the analyses with the full study cohort, and

increased risk for rehospitalization for hyperkalemia,

findings remained consistent with the original anal-

and more than one-third of patients were no longer

ysis. Moreover, given the low event rate and other

taking the MRA 6 months post-discharge (18). In the

demographic discrepancies in these regions, restric-

TOPCAT trial, discontinuations of participants in the

tion of our analysis to the Americas is more likely to

infarction

found

an

almost

placebo group did not increase with age, whereas

accurately reflect patients with HFpEF. Despite this

discontinuations

spi-

selection, TOPCAT uniquely enrolled >40% of pa-

ronolactone were highest among participants over

tients above the age of 75 years, improving precision

age 75 years, also supporting a higher risk for adverse

of estimates of safety and efficacy of spironolactone

effects with spironolactone with age. Trial in-

among older adults.

of

those

randomized

to

vestigators may have been more attuned to tolerability issues with older participants and more likely to

CONCLUSIONS

discontinue study medication at lower thresholds when confronted with potential adverse effects

In this post hoc, exploratory analysis of the TOPCAT

compared with younger individuals. This hypothesis

trial data from the Americas region, although there

is supported by the fact that doses of spironolactone,

was no effect of age on efficacy, there were consid-

but not placebo, were lower during trial follow-up in

erable effects of age on increased rates of adverse

patients in the older age categories. As such, rates for

safety outcomes. This occurred despite careful,

hyperkalemia, for example, appear highest in the

protocol-mandated monitoring during the trial and

middle age group because those in the highest age

despite lower final doses in the older age groups.

group were more likely to be off study medication.

These results should be weighed when considering

Our findings suggest that there is greater chance, in relative terms, of patients older than age 65 experi-

spironolactone for older patients with HFpEF in clinical practice.

encing significant adverse safety outcomes from spironolactone than from being protected against the

ADDRESS FOR CORRESPONDENCE: Dr. Orly Var-

primary outcome. This altered risk-benefit profile in

deny, Minneapolis VA Center for Care Delivery and

older adults compared with individuals younger than

Outcomes Research, University of Minnesota, One

age 65 requires careful consideration by clinicians

Veterans

assessing patients of all ages with HFpEF for potential

E-mail: [email protected].

Drive,

Minneapolis,

Minnesota

55417.

1027

1028

Vardeny et al.

JACC: HEART FAILURE VOL. 7, NO. 12, 2019 DECEMBER 2019:1022–8

Spironolactone in Older Adults With HFpEF

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: The use

TRANSLATIONAL OUTLOOK: The use of MRAs in

of MRAs are recommended by heart failure guidelines in

clinical practice is suboptimal, in part due to concerns for

appropriately selected individuals with HFpEF. Whether

varying efficacy among subgroups of patients and po-

the efficacy or safety of MRAs differs by age is unclear.

tential medication-related toxicity. Although our study

Findings from this study support consistent efficacy of

found that the benefit of spironolactone is maintained in

spironolactone across the age spectrum but a magnified

different age groups, the increased risk for discontinua-

risk for discontinuation due to hyperkalemia and wors-

tion due to adverse effects suggests the need for an

ening renal function in older individuals. These data

individualized monitoring strategy in older patients and

support the potential benefits of spironolactone in pa-

additional research on the safe implementation of these

tients with HFpEF and emphasize the importance of

medications.

judicious monitoring to reduce the risk for MRA-related adverse effects and toxicity.

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KEY WORDS age, heart failure with preserved ejection fraction, mineralocorticoid receptor antagonists, spironolactone A PPE NDI X For supplemental tables and a figure, please see the online version of this paper.