Introduction
Cardiovascular disease accounts for most of the deaths in patients receiving maintenance hemodialysis (HD).1 Approximately half of cardiovascular mortality events are attributed to sudden cardiac death,1 and adverse cardiac events (including dysrhythmia) occur with greater frequency on days during which HD is performed.2–5 The development of arrhythmia is hypothesized to be a major risk factor for sudden cardiac death, and the frequency of arrhythmic events also seems to be temporally related to the HD schedule.6
While inhibitors of the renin-angiotensin-aldosterone system have been shown to reduce morbidity and mortality in non-HD patients with a variety of cardiac pathologies,7–10 evidence supporting the use of renin-angiotensin-aldosterone system inhibition in patients requiring maintenance HD is less clear.11,12 Aldosterone is known to be a key mediator of adverse myocardial remodeling and fibrosis,13 processes that may predispose to arrhythmias. As aldosterone concentrations are often elevated in HD patients, there is a biologic rationale for pharmacologic blockade of the mineralocorticoid receptor. However, enthusiasm for using mineralocorticoid receptor antagonists in patients receiving HD is tempered by concerns about hyperkalemia.14,15
The Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD (SPin-D) study was a double-blind randomized clinical trial designed to assess safety and tolerability of three doses of spironolactone versus placebo in patients receiving maintenance HD (n=129).16 Overall, spironolactone was well tolerated, with no major difference in the frequency of hyperkalemia >6.5 mEq/L or serious hypotension compared with placebo but had no detectable effect on measures of diastolic function in exploratory efficacy analyses. A subset of 57 SPin-D participants underwent continuous electrocardiographic monitoring for 7-day periods at baseline, 6 weeks, and/or between weeks 32–36, using a wearable device. Post hoc analysis of electrocardiographic data allowed us to test the hypothesis that spironolactone reduces the risk of arrhythmic events, compared with placebo.
Methods
SPin-D was a parallel-group, double-blind, randomized, multiple-dosage trial designed to test the safety and tolerability of spironolactone versus placebo in adult patients receiving maintenance HD (NCT02285920). Participants were enrolled from 13 HD units affiliated with four academic medical centers in the United States and were randomized in a 2:1:1:1 ratio to placebo or spironolactone 12.5, 25, or 50 mg daily for 36 weeks. The institutional review boards affiliated with each site approved the protocol, and each participant provided written informed consent.
Study Population and Procedures
SPin-D enrolled 129 participants who met the following inclusion criteria: age 18–85 years and treatment with maintenance HD for >6 months or for 3–6 months if there were no changes in target dry weight during the prior 2 weeks and no hospitalizations during the previous 6 weeks. Notable exclusion criteria included serum potassium concentration ≥6.5 mEq/L or unscheduled dialysis for hyperkalemia within 3 months; serum potassium concentration ≥6.0 mEq/L within 2 weeks before baseline; pre-HD systolic blood pressure <100 mm Hg within 2 weeks before screening or at baseline; ≥2 dialysis sessions within the month before screening with blood pressure <80 mm Hg or treatment for cramping, light-headedness, nausea, or hypotension; use of digoxin, spironolactone, or eplerenone; or dual use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
A protocol amendment was added on January 22, 2016, after 64 patients had enrolled in the trial to include optional cardiac monitoring during trial participation. A subset of 57 patients consented to undergo seven days of continuous heart rate and rhythm monitoring using a wearable patch (SEEQ Mobile Cardiac Telemetry System; Medtronic, Minneapolis, MN) before randomization, at week 6, and during weeks 32–36. Thirty (53%) of the 57 participants completed electrocardiographic monitoring at all three time points.
Exposures and Outcomes
The primary exposure for these post hoc subgroup analyses was the randomized treatment arm, with comparisons of the individual dosage arms of spironolactone with placebo. The secondary exposure of interest was spironolactone, regardless of dose, evaluated by combining the three spironolactone groups for comparisons with placebo.
The Medtronic SEEQ devices were preprogrammed to detect 26 arrhythmia events. Because some of the arrhythmia events were rare, the outcomes for the present analyses considered six aggregated categories of arrhythmia events as follows: (1) atrial fibrillation/flutter on ≥41 of 45 consecutive beats at ≥150 beats per minute; (2) ventricular arrhythmia defined as polymorphic or monomorphic ventricular tachycardia on ≥18 of 20 beats; (3) conduction blocks defined as asystole >3 seconds, first degree atrioventricular block, second degree atrioventricular block, or junctional rhythm or intraventricular conduction delay; (4) bradycardia defined as <40 beats per minute on four of five consecutive beats; (5) atrial/sinus or other nonventricular tachycardias; and (6) conduction blocks or bradycardia (Supplemental Table 1).
Study Data
Baseline data for trial participants were obtained through self-report, medical record review, and questionnaires. In addition to blood for batched analyses collected at baseline and at 36 weeks, pre-HD serum potassium concentration was measured at the following time points: every month; 3–5 days and 2 weeks after each study drug dose increase; and within 1 week after any hyperkalemia events (defined as any serum potassium concentration >6.0 mEq/L, whether obtained for the trial or for clinical purposes). Echocardiography was performed at baseline and at the end of follow-up.
Statistical Analyses
Continuous variables were examined graphically and recorded as mean (± SD) for normally distributed data or median (with 25th and 75th percentile) for non-normally distributed data. Categorical variables were examined by frequency distribution and recorded as proportions. Differences across randomized treatment arms were assessed using analysis of variance, chi-squared test, or Kruskal-Wallis tests, as appropriate.
Crude recurrent arrhythmia events were presented as frequency (%) and incidence rate (per 100 patient-days) by treatment groups at baseline, week 6, and the end of study. P-values for linear trends using equally spaced scores, and for comparisons between the combined spironolactone groups and placebo group, were determined using generalized estimating equations with independent correlation structure accounting for clustering effect of centers and participants: specifically, Poisson distribution with a log link for recurrent arrythmia events. Models included the exposure of interest (i.e., treatment groups), discrete study visits, trial randomization stratification factors of time since initiating dialysis (<1 or ≥1 year), and current angiotensin converting enzyme inhibitor or angiotensin receptor blocker use (yes/no). Rate ratios (RRs) for recurrent arrhythmia events were estimated from the generalized estimating equations models for the composite of atrial fibrillation or flutter and the composite of bradycardia or conduction blocks. Estimated RRs for other arrhythmia events were not generated because of insufficient numbers of events. Exploratory analyses were also performed to determine the association of various predictors with the composite outcomes of atrial fibrillation/flutter and bradycardia or conduction block. To avoid overfitting, the number of covariates included in the adjusted models was based, in part, on the frequency of outcome events.
All analyses were performed using SAS version 9.4 (SAS Institute Inc.) and geepack package in R version 3.4.3 (https://www.r-project.org). Given the pilot nature of the current analyses, with a focus on exploration, no corrections were made for multiple comparisons.
Results
Baseline Characteristics
The baseline characteristics of the SPin-D participants who did (n=57) and did not (n=72) take part in the electrocardiographic monitoring substudy are presented in Supplemental Table 2. Of those included in this analysis, most of the participants were Black (77%), 61% were male, the mean age was 55±12 years, and the median duration on HD was 3.4 (25th–75th percentile 1.9–6.9) years. The baseline characteristics were similar among the four randomized treatment arms (Table 1) and in the combined spironolactone and placebo groups (Supplemental Table 3). The baseline echocardiographic parameters were generally similar across randomized treatment arms, with the exception of left ventricular (LV) end-diastolic diameter and body surface area–adjusted LV mass, which were both lower in the 50 mg spironolactone group (Supplemental Table 4).
Table 1 -
Baseline characteristics
| Characteristic |
All (n=57) |
Placebo (n=21) |
Spironolactone 12.5 mg (n=11) |
Spironolactone 25 mg (n=12) |
Spironolactone 50 mg (n=13) |
| Male, n (%) |
35 (61.4) |
13 (61.9) |
4 (36.4) |
8 (66.7) |
10 (76.9) |
| Age, yr; mean (SD) |
55.3 (12.1) |
53.8 (10.8) |
52.7 (16.8) |
58.8 (13.3) |
56.6 (7.9) |
| Black, n (%) |
44 (77.2) |
18 (85.7) |
8 (72.7) |
9 (75.0) |
9 (69.2) |
| White, n (%) |
7 (12.3) |
0 (0.00) |
3 (27.3) |
2 (16.7) |
2 (15.4) |
| Asian, n (%) |
3 (5.3) |
1 (4.8) |
0 (0.00) |
1 (8.3) |
1 (7.7) |
| Hispanic/Latino, n (%) |
5 (8.8) |
2 (9.5) |
2 (18.2) |
0 (0.00) |
1 (7.7) |
| BMI, kg/m2; mean (SD) |
32.6 (7.9) |
30.4 (6.5) |
33.6 (10.7) |
33.1 (8.7) |
34.7 (6.5) |
| Systolic BP, mm Hg; mean (SD) |
138.7 (22.2) |
140.6 (24.1) |
134.5 (16.9) |
138.9 (30.0) |
139.2 (15.6) |
| Diastolic BP, mm Hg; mean (SD) |
75.1 (10.1) |
74.7 (8.2) |
72.5 (8.9) |
73.7 (9.5) |
79.2 (13.9) |
| Hypertension, n (%) |
55 (96.5) |
21 (100.0) |
11 (100.0) |
11 (91.7) |
12 (92.3) |
| Diabetes mellitus, n (%) |
36 (63.2) |
12 (57.1) |
7 (63.6) |
7 (58.3) |
10 (76.9) |
| Coronary artery disease, n (%) |
18 (31.6) |
6 (28.6) |
1 (9.1) |
5 (41.7) |
6 (46.2) |
| Congestive heart failure, n (%) |
10 (17.5) |
3 (14.3) |
2 (18.2) |
3 (25.0) |
2 (15.4) |
| Atrial fibrillation, n (%) |
5 (8.8) |
3 (14.3) |
0 (0.00) |
2 (16.7) |
0 (0.00) |
| Stroke, n (%) |
10 (17.5) |
6 (28.6) |
2 (18.2) |
0 (0.00) |
2 (15.4) |
| Peripheral vascular disease, n (%) |
11 (19.3) |
3 (14.3) |
2 (18.2) |
4 (33.3) |
2 (15.4) |
| Hyperlipidemia, n (%) |
28 (49.1) |
9 (42.9) |
6 (54.5) |
6 (50.0) |
7 (53.8) |
| Current tobacco use, n (%) |
8 (14.0) |
3 (14.3) |
1 (9.1) |
1 (8.3) |
3 (23.1) |
| AV graft, n (%) |
7 (12.3) |
2 (9.5) |
4 (36.4) |
0 (0.00) |
1 (7.7) |
| AV fistula, n (%) |
48 (84.2) |
19 (90.5) |
7 (63.6) |
11 (91.7) |
11 (84.6) |
| Tunneled CVC, n (%) |
1 (1.8) |
0 (0.00) |
0 (0.00) |
0 (0.00) |
1 (7.7) |
| Other, n (%) |
1 (1.8) |
0 (0.00) |
0 (0.00) |
1 (8.3) |
0 (0.00) |
| Dialysis vintage, yr; median 25th-75th percentile |
3.4 (1.9–6.9) |
3.9 (2.2–10.4) |
1.5 (1.0–3.7) |
3.6 (2.8–5.5) |
3.4 (2.2–4.9) |
| Dialysis ≥1 year, n (%) |
52 (91.2) |
20 (95.2) |
8 (72.7) |
12 (100.0) |
12 (92.3) |
| ACEI or ARB use, n (%) |
18 (31.6) |
7 (33.3) |
3 (27.3) |
3 (25.0) |
5 (38.5) |
| Beta blockers use, n (%) |
31 (54.4) |
11 (52.4) |
6 (54.5) |
6 (50.0) |
8 (61.5) |
| Statins use, n (%) |
30 (52.6) |
9 (42.9) |
7 (63.6) |
7 (58.3) |
7 (53.8) |
| Antiplatelet agents use, n (%) |
25 (43.9) |
8 (38.1) |
5 (45.5) |
6 (50.0) |
6 (46.2) |
| Single pool Kt/V; mean (SD) |
1.6 (0.4) |
1.4 (0.2) |
1.5 (0.2) |
1.6 (0.4) |
1.8 (0.6) |
| 24-h urine volume, ml; mean (SD)
a
|
202.5 (299.8) |
205.7 (345.1) |
182.1 (233.2) |
255.7 (372.0) |
169.9 (226.0) |
Sample sizes in the header represent numbers of patients with at least one monitoring done at baseline, week 6, or the end of study. There were no statistically significant differences between groups at baseline. BMI, body mass index; AV, arteriovenous; CVC, central venous catheter; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
aValues determined for 55 of the 57 participants.
Arrhythmia Events at Baseline, 6 Weeks, and End of Follow-Up, According to Randomized Treatment Arm
Among the 35 SPin-D participants who underwent electrocardiographic monitoring at baseline, nine of 14 (64%) in the placebo group and six of 21 (29%) in the combined spironolactone group had at least one arrhythmia event during the baseline monitoring period (Figure 1 and Table 2). Most of these events were atrial/sinus and other nonventricular tachycardias, followed in frequency by atrial fibrillation/flutter, and conduction blocks (frequency of individual events are provided in Supplemental Tables 5-9). Overall arrhythmia event rates at baseline were lower for the individual and combined spironolactone groups, compared with placebo (Supplemental Table 10).
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Figure 1: Arrhythmia event rates by treatment groups and study visits. SPL, spironolactone.
Table 2 -
Crude
arrhythmia events
| Arrhythmia Type |
Placebo (n=21) |
Spironolactone Groups Combined (n=36) |
Spironolactone 12.5 mg (n=11) |
Spironolactone 25 mg (n=12) |
Spironolactone 50 mg (n=13) |
| Pts w/Event n (%) |
Events per 100 Pt-Days |
Pts w/Event n (%) |
Events per 100 Pt-Days |
Pts w/Event n (%) |
Events per 100 Pt-Days |
Pts w/Event n (%) |
Events per 100 Pt-Days |
Pts w/Event n (%) |
Events per 100 Pt-Days |
| Baseline |
Monitoring done, n
|
14 |
21 |
8 |
6 |
7 |
| Atrial fibrillation/flutter |
2 (14.3) |
13.8 |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
| Ventricular arrhythmia |
1 (7.1) |
0.9 |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
| Conduction block |
3 (21.4) |
5.5 |
1 (4.8) |
0.6 |
0 (0.0) |
0 |
1 (16.7) |
2.1 |
0 (0.0) |
0 |
| Bradycardia |
1 (7.1) |
0.9 |
1 (4.8) |
0.6 |
0 (0.0) |
0 |
0 (0.0) |
0 |
1 (14.3) |
1.9 |
| Atrial/sinus/other nonventricular tachycardia |
4 (28.6) |
25.7 |
4 (19.0) |
7.5 |
2 (25.0) |
11.9 |
1 (16.7) |
8.5 |
1 (14.3) |
1.9 |
| Bradycardia or conduction block |
4 (28.6) |
6.4 |
2 (9.5) |
1.3 |
0 (0.0) |
0 |
1 (16.7) |
2.1 |
1 (14.3) |
1.9 |
| Any arrhythmia events |
9 (64.3) |
53.2 |
6 (28.6) |
10.1 |
2 (25.0) |
11.9 |
2 (33.3) |
12.8 |
2 (28.6) |
5.7 |
| Week 6 |
Monitoring done, n
|
14 |
23 |
8 |
6 |
9 |
| Atrial fibrillation/flutter |
2 (15.4) |
17.2 |
3 (13.0) |
5.2 |
0 (0.0) |
0 |
0 (0.0) |
0 |
3 (33.3) |
13.2 |
| Ventricular arrhythmia |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
0 (0.0) |
0 |
| Conduction block |
1 (7.7) |
1.0 |
5 (21.7) |
7.5 |
2 (25.0) |
3.2 |
1 (16.7) |
2.4 |
2 (22.2) |
14.7 |
| Bradycardia |
1 (7.7) |
3.0 |
4 (17.4) |
6.4 |
2 (25.0) |
3.2 |
0 (0.0) |
0 |
2 (22.2) |
13.2 |
| Atrial/sinus/other nonventricular tachycardia |
2 (15.4) |
4.0 |
5 (21.7) |
16.2 |
2 (25.0) |
20.6 |
1 (16.7) |
2.4 |
2 (22.2) |
20.6 |
| Bradycardia or conduction block |
2 (15.4) |
4.0 |
7 (30.4) |
13.9 |
3 (37.5) |
6.3 |
1 (16.7) |
2.4 |
3 (33.3) |
27.9 |
| Any arrhythmia events |
4 (30.8) |
29.3 |
11 (47.8) |
49.1 |
3 (37.5) |
33.3 |
2 (33.3) |
7.1 |
6 (66.7) |
89.7 |
| End of study |
Monitoring done, n
|
21 |
32 |
9 |
11 |
12 |
| Atrial fibrillation/flutter |
4 (19.0) |
7.1 |
4 (12.5) |
9.7 |
1 (11.1) |
2.9 |
1 (9.1) |
9.9 |
2 (16.7) |
15.4 |
| Ventricular arrhythmia |
1 (4.8) |
1.3 |
1 (3.1) |
0.4 |
0 (0.0) |
0 |
0 (0.0) |
0 |
1 (8.3) |
1.3 |
| Conduction block |
13 (61.9) |
38.7 |
20 (62.5) |
76.2 |
7 (77.8) |
69.1 |
6 (54.5) |
61.7 |
7 (58.3) |
97.4 |
| Bradycardia |
0 (0.0) |
0 |
1 (3.1) |
6.2 |
0 (0.0) |
0 |
0 (0.0) |
0 |
1 (8.3) |
17.9 |
| Atrial/sinus/other nonventricular tachycardia |
8 (38.1) |
14.2 |
11 (34.4) |
16.3 |
3 (33.3) |
7.4 |
4 (36.4) |
18.5 |
4 (33.3) |
21.8 |
| Bradycardia or conduction block |
13 (61.9) |
38.7 |
20 (62.5) |
82.4 |
7 (77.8) |
69.1 |
6 (54.5) |
61.7 |
7 (58.3) |
115.4 |
| Any arrhythmia events |
18 (85.7) |
100.0 |
25 (78.1) |
191.2 |
7 (77.8) |
148.5 |
9 (81.8) |
151.9 |
9 (75.0) |
269.2 |
Sample sizes in the header represent numbers of patients with at least one monitoring done at baseline, week 6, or the end of study. Pts, participants.
A total of 37 patients underwent electrocardiographic monitoring at 6 weeks. The proportion of patients with any event was 31% (4 of 14 patients) in the placebo group and 48% (11 of 23 patients) in the combined spironolactone group (Figure 1 and Table 2). There were no major differences in event rates based on the randomized treatment groups at the 6-week time point (Supplemental Table 10).
A total of 53 patients underwent electrocardiographic monitoring at the end of follow-up. The proportion of patients with any event was 86% (18 of 21 patients) in the placebo group and 78% (25 of 32 patients) in the combined spironolactone group (Figure 1 and Table 2). The combined spironolactone group had a higher rate of bradycardia or conduction blocks, compared with the placebo group (82.4 events per 100 patient-days versus 38.7 events per 100 patient-days; P<0.001 [Supplemental Table 10]).
Ventricular events were rare during the baseline, 6-week, and end of follow-up monitoring periods.
Effect of Spironolactone Versus Placebo on Atrial Fibrillation/Flutter and Bradycardia or Conduction Blocks
The higher frequency of atrial fibrillation/flutter and bradycardia or conduction block events, compared with other events, permitted the estimation of RRs, according to the randomized groups. There were no significant associations of spironolactone (individual dose groups or combined) with atrial fibrillation/flutter, compared with placebo (Table 3).
Table 3 -
Estimated rate ratios (95% confidence intervals) for atrial fibrillation/flutter and bradycardia/conduction blocks, according to randomized treatment group
| Model |
Exposure |
Atrial Fibrillation or Atrial Flutter
a
|
Bradycardia or Conduction Blocks
b
|
| 1 |
Spironolactone 12.5 mg vs placebo |
0.09 (0.01–1.04) |
1.56 (0.73–3.34) |
| Spironolactone 25 mg vs placebo |
0.40 (0.03–5.01) |
1.45 (0.61–3.44) |
| Spironolactone 50 mg vs placebo |
0.89 (0.11–6.96) |
3.00 (0.80–11.20) |
| 2 |
Spironolactone combined vs placebo |
0.47 (0.07–3.21) |
2.04 (0.83–5.05) |
aModels (independence correlation) included the exposure of interest and study visits.
bModels (independence correlation) included the exposure of interest, study visits, length of time on dialysis, and current angiotensin converting enzyme inhibitor/angiotensin receptor blocker use.
A dose-related, but nonsignificant, increase in bradycardia or conduction block events with spironolactone was observed, with a RR of 3.0 (95% confidence interval [CI] 0.80–11.20) for the 50 mg group and 1.45 (95% CI 0.61–3.44) for the 25 mg group, compared with placebo. Similarly, there was an approximately two-fold higher risk of bradycardia or conduction block events for the combined spironolactone group versus placebo (RR 2.04; 95% CI 0.83–5.05 [Table 3]). In a sensitivity analysis, examining only patients with available baseline and follow-up data (n=33), the combined spironolactone group again had a nominally higher, but nonsignificant, risk of bradycardia or conduction block events, compared with placebo (RR 1.80 [95% CI, 0.82 to 3.97]).
Exploratory Analyses for the Association of Other Variables of Interest with Atrial Fibrillation/Flutter and Bradycardia or Conduction Blocks
Exploratory analyses were performed to evaluate associations of variables of interest including hyperkalemia, intradialytic hypotension, ultrafiltration volume, and echocardiographic measures, with risks of atrial fibrillation/flutter and bradycardia or conduction blocks. Higher baseline left atrial diameter was associated with an increased risk of atrial fibrillation/flutter (RR, 3.02; 95% CI, 1.13 to 8.07), but not with bradycardia or conduction block (RR, 1.64; 95% CI, 0.62 to 4.34). Although hyperkalemia within the prior 7 days (versus none) had the highest effect estimate for risk of bradycardia or conduction block events, this did not reach statistical significance (RR, 2.07; 95% CI, 0.52 to 8.25). Effect estimates for the association of hyperkalemia (defined in several ways) with atrial fibrillation/flutter were also nonsignificant [Supplemental Table 11]).
Discussion
In this post hoc analysis of cardiac rhythm monitoring performed in a subset of participants in the SPin-D trial, we found that spironolactone resulted in a higher frequency of bradycardic or conduction block events compared with placebo and that this risk was most pronounced at the highest evaluated dose of 50 mg/d. However, adjusted effect estimates, while directionally consistent with the crude observations, did not meet statistical significance.
Although one of the major effects of mineralocorticoid receptor stimulation by aldosterone is to promote renal sodium reabsorption and potassium secretion in the distal nephron, the mineralocorticoid receptor is known to be present in many other cell types, with overactivation being associated with development of fibrosis of the heart,17 vasculature,18 and kidney.19,20 In animal models, blockade of the mineralocorticoid receptor has been shown to ameliorate LV hypertrophy and myocardial fibrosis,21–24 providing additional support for a potential pathogenic role of excessive aldosterone concentrations. Cardiac structural abnormalities are common in patients initiating HD25 and are often characterized by myocardial fibrosis and reduced capillary density, compared with normal and hypertensive controls.26 This constellation of findings may predispose to the development of myocardial hypoxia and conduction system dysfunction, generating conditions for the development of arrhythmia.27 In light of these associations, and the presence of elevated aldosterone concentrations in patients receiving maintenance HD,28,29 there has been much interest in the use of mineralocorticoid receptor antagonists as a potential therapeutic option to reduce adverse cardiovascular outcomes in this high-risk patient population.
Atrial fibrillation is the most common clinically evident arrhythmia in HD patients and has been found to occur in up to 40% of patients in studies using implantable loop recorders.6,30,31 In the non-HD population, the evidence supporting the use of mineralocorticoid receptor antagonists to prevent atrial fibrillation is somewhat conflicting. While several systematic reviews and meta-analyses of randomized controlled trials and observational studies have suggested a beneficial association of such agents for the reduction of new-onset and recurrent atrial fibrillation,32,33 in contrast, a post hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial did not find evidence for beneficial effects of spironolactone on reduction of incident atrial fibrillation in patients with heart failure and preserved ejection fraction.34 In this respect, it is notable that the mean left ventricular ejection fraction in this study was 67.5%. Trials testing the ability of mineralocorticoid receptor antagonists to reduce arrhythmic risk in patients with ESKD are lacking, but observational data have suggested a decreased risk of new-onset atrial fibrillation among those prescribed, compared with those not prescribed, spironolactone.35 In this study, which was limited by baseline between-group differences in event rates and low overall event rates, an effect of spironolactone on atrial fibrillation was not detected.
Recent studies using implantable loop recorders in patients receiving maintenance HD have consistently reported a relatively high frequency of bradycardic and conduction block events.6,36–39 In the present analyses, we observed a two-fold higher risk of bradycardic and conduction block events with spironolactone use, particularly for the 50 mg dose, compared with placebo at the end of the study, despite a baseline event rate that was higher in the placebo group. Previous studies have reported associations between higher pre-HD serum potassium concentrations and greater risk of arrhythmia-related hospitalizations or sudden death.40 Furthermore, data from some implantable loop recorder studies have suggested a higher risk of conduction block/bradycardia with hyperkalemia,38 suggesting a potential pathophysiological mechanism that may underlie these observations. While the primary analysis of SPin-D reported no major difference in the frequency of the two primary safety endpoints (hyperkalemia >6.5 mEq/L and serious hypotension) between the combined spironolactone group and placebo, there were trends toward higher frequency of hyperkalemic events with the highest (50 mg) spironolactone dose.16 Similarly, the Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease trial (n=97), which tested 50 mg spironolactone against placebo over the 40-week follow-up, reported that moderate hyperkalemia (6.0–6.5 mEq/L) was more common in the spironolactone group, but severe hyperkalemia (>6.5 mEq/L) was not.15 Similar trends toward higher risks of hyperkalemia were noted in a trial of eplerenone, compared with placebo.14 Although nonsignificant and hypothesis-generating, the present findings suggest close monitoring of serum potassium concentration in patients treated with maintenance HD who are prescribed mineralocorticoid receptor antagonists is reasonable while more definitive data are awaited.
There are notable strengths to our present analyses, including the use of continuous electrocardiographic monitoring, the evaluation of multiple doses of spironolactone with placebo comparisons, and the recruitment and detailed follow-up of patients from multiple centers in the setting of a randomized controlled trial. However, there are several limitations to be acknowledged. Only a subset of SPin-D participants were included in the continuous monitoring component of the trial, follow-up was relatively short, and patients were younger and had better preservation of ejection fraction than the overall HD population in the United States, thus limiting generalizability. Not all patients in the monitoring substudy contributed arrhythmia data at all time points, raising the possibility of some element of selection bias and precluding analyses according to the interdialytic interval. Furthermore, the small sample size and lack of blood collection that was standardized with respect to the timing of the rhythm monitoring periods limited the ability to conduct explanatory and mechanistic analyses. Finally, owing to the modest sample size, the categories of prespecified arrhythmias were necessarily broad with small numbers of events precluding meaningful subgroup analyses—thus, the relative clinical importance of subtypes within a category may also not be comparable.
In summary, in this post hoc analysis of SPin-D, those who received spironolactone had a higher risk of bradycardia or conduction blocks, as assessed by continuous electrocardiography, compared with those who received placebo. However, while hypothesis-generating, the present analyses were underpowered and should be interpreted as such while we await the results of definitive trials examining hard clinical endpoints (NCT01848639 and NCT03020303).
Disclosures
D.M. Charytan—expert witness fees related to dialysate composition-Fresenius Research Support-Medtronic. Research support and consulting fees related to services as national investigator, trial steering committee, or data monitoring committee-Zoll Medical, Allena Pharmaceuticals, AstraZeneca, Janssen Pharmaceuticals, Gilead Pharmaceuticals, and Novo Nordisk. Consulting fees and travel support-Medtronic/Covidien, Amgen, Daichi, Fresenius, Merck, and Sankyo. L.M. Dember receives compensation from the National Kidney Foundation for her role as Deputy Editor of the American Journal of Kidney Diseases and consulting fees from Merck, AstraZeneca, and Cara Therapeutics. J. Himmelfarb is a founder and holds equity in Kuleana Technology, Inc. J.Y. Hsu reports the following: advisory or leadership role—AJKD, Statistics/Epidemiology Editor; PLOS ONE, Statistical Advisory Board; and American Medical Association, Statistical Reviewer. T.A. Ikizler reports the following—consultancy: Abbott Renal Care, Fresenius-Kabi, Nestle, and La Renon; honoraria: IAbbott Renal Care, Fresenius-Kabi, Nestle, and La Renon; patents or royalties: Vanderbilt University Medical Center; and advisory or leadership role: Kidney International. P.L. Kimmel reports the following—ownership interest: As a Federal Employee at NIDDK, my holdings are reviewed each year for potential conflict of interest. At this time, my only stock holding related in any fashion to health care is CVS; patents or royalties: Elsevier; royalties for co-editing Chronic Renal Disease and Psychosocial Aspects of Chronic Kidney Disease; advisory or leadership role: unpaid member of Board of Directors of Academy of Medicine of Washington, DC; and other interests or relationships: Co-Editor, Chronic Renal Disease Academic Press; Co-Editor, Psychosocial Aspects of Chronic Kidney Disease. A.S. Kliger reports the following—consultancy: ASN; ownership interest: multiple equity positions managed by UBS; advisory or leadership role: American Society of Nephrology; Chair, EPC Advisory Committee; and other interests or relationships: Renal Physicians Association and American Society of Nephrology. F.R. Mc Causland notes consulting fees from Advanced Medical, Zydus Therapeutics, and GlaxoSmithKline, research support from NIDDK, Satellite Healthcare, and research grants from Fifth Eye and Advanced Instruments paid directly to his institution. R. Mehrotra reports the following—consultancy: Light Line Medical; advisory or leadership role: Editor-in-Chief, Clinical Journal of the American Society of Nephrology; president-elect, International Society for Peritoneal Dialysis; Chair, Nephrology Longitudinal Assessment Approval Committee of the American Board of Internal Medicine; Editorial Board for Journal of Renal Nutrition, Peritoneal Dialysis International; and other interests or relationships: Chair, Board of Trustees, Northwest Kidney Centers. D.S. Raj reports the following—consultancy: Novo Nordics; research funding: NIH; honoraria: Novo Nordics; advisory or leadership role: NIDDK; NHLBI; Novo Nordics; and other interests or relationships: American Association of Kidney Patients. S.S. Waikar reports personal fees from Public Health Advocacy Institute, Barron, Budd (versus Fresenius), Bunch, CVS, GE Health Care, GSK, JNJ, Kantum Pharma, Mallinckrodt, Mass Medical International, Roth Capital Partners, Takeda, Strataca, Wolters Kluwer, venBio, Pfizer, Bain, Biomarin, Harvard Clinical Research Institute (also known as Baim), James, Metro Biotechnology, Oxidien, Regeneron, and Sironax and grants and personal fees from Allena Pharmaceuticals, outside the submitted work.
Funding
This trial was funded by the following cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases: U01 DK096189, U01 DK099923, U01 DK099914, and U01DK099919. Additional support was provided by the Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1TR001102) and financial contributions from Harvard University and its affiliated academic health care centers. The SEEQ Mobile Cardiac Telemetry (MCl) Systems used for heart rate and rhythm monitoring were donated by Medtronic Inc.
Acknowledgments
Project officers from the National Institute of Diabetes and Digestive and Kidney Diseases worked collaboratively with the investigators in designing the study, monitoring the study performance, interpreting data, and preparing the manuscript. Medtronic Inc. had no involvement in designing or conducting the study, analyzing or interpreting the data, or preparing the article. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic health care centers. The authors would like to thank the participating patients, dialysis unit personnel, and dialysis provider organizations for their important contributions to this work.
The opinions expressed are those of the authors and do not necessarily reflect those of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, the Department of Health and Human Services, or the government of the United States.
Portions of these results were presented at the 2019 American Society of Nephrology Kidney Week in Washington DC.
Author Contributions
Conceptualization: David Charytan, Laura Dember, Jonathan Himmelfarb, T. Alp Ikizler, Paul Kimmel, Alan Kliger, Rajnish Mehrotra, Dominic Raj
Formal analysis: Jesse Hsu, Finnian Mc Causland
Investigation: David Charytan, Laura Dember, Jonathan Himmelfarb, T. Alp Ikizler, Paul Kimmel, Alan Kliger, Rajnish Mehrotra, Dominic Raj, Sushrut Waikar
Methodology: Finnian Mc Causland
Project administration: Laura Dember
Supervision: David Charytan, Laura Dember
Writing - original draft: Finnian Mc Causland
Writing - review and editing: David Charytan, Laura Dember, Jonathan Himmelfarb, Jesse Hsu, T. Alp Ikizler, Paul Kimmel, Alan Kliger, Rajnish Mehrotra, Dominic Raj, Sushrut Waikar
Data Sharing Statement
Anonymized data created for the study are or will be available in a persistent repository on publication: Analyzable Data, NIDDK Repository.
Supplemental Material
This article contains the following supplemental material online at https://links.lww.com/KN9/A315.
Supplemental Table 1. Preprogrammed arrhythmia events detected by the Medtronic SEEQ device and a priori aggregated arrhythmia events.
Supplemental Table 2. Characteristics of the SPin-D trial participants at baseline according to participation or nonparticipation in the electrocardiographic monitoring substudy.
Supplemental Table 3. Characteristics of the patients at baseline, according to the combined spironolactone arms or placebo.
Supplemental Table 4. Characteristics of echocardiography at baseline, according to the randomized treatment assignment.
Supplemental Table 5. Aggregated and individual conduction block events.
Supplemental Table 6. Aggregated and individual atrial fibrillation/flutter events.
Supplemental Table 7. Aggregated and individual ventricular arrhythmia events.
Supplemental Table 8. Aggregated and individual bradycardia events.
Supplemental Table 9. Aggregated and individual atrial/sinus/other nonventricular tachycardia events.
Supplemental Table 10. Arrhythmia event rates (per 100 patient-days) and 95% confidence intervals.
Supplemental Table 11. Estimated rate ratios (95% CIs) of other exposures of interest for atrial fibrillation/flutter and bradycardia/conduction blocks.
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