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Randomized Controlled Trial
. 2021 Oct;16(10):1491-1501.
doi: 10.2215/CJN.01930221. Epub 2021 Aug 30.

Effects of Spironolactone and Chlorthalidone on Cardiovascular Structure and Function in Chronic Kidney Disease: A Randomized, Open-Label Trial

Nicola C Edwards  1   2 , Anna M Price  1   3 , Samir Mehta  4 , Thomas F Hiemstra  5   6 , Amreen Kaur  1 , Peter J Greasley  7 , David J Webb  8 , Neeraj Dhaun  8   9 , Iain M MacIntyre  8   9 , Tariq Farrah  8   9 , Vanessa Melville  8 , Anna S Herrey  10 , Gemma Slinn  4 , Rebekah Wale  4 , Natalie Ives  4 , David C Wheeler  11   12 , Ian Wilkinson  5   6 , Richard P Steeds  1   13 , Charles J Ferro  1   3 , Jonathan N Townend  1   13
Affiliations
Randomized Controlled Trial

Effects of Spironolactone and Chlorthalidone on Cardiovascular Structure and Function in Chronic Kidney Disease: A Randomized, Open-Label Trial

Nicola C Edwards et al. Clin J Am Soc Nephrol. 2021 Oct.

Abstract

Background and objectives: In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone.

Design, setting, participants, & measurements: A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m2). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg).

Results: There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g, P=0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s, P=0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, P=0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, P=0.07).

Conclusions: Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.

Keywords: aldosterone; cardiovascular system; chlorthalidone; chronic kidney disease; randomized controlled trials; spironolactone.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram: Eligibility, randomization, and follow-up. *Side effects leading to patient withdrawal of spironolactone: inflamed gums, symptomatic hyponatremia, and worsening of polymyalgia rheumatica and back and leg pain. Side effects leading to patient withdrawal of chlorthalidone: dizziness and headache, too many unwanted side effects from being on irbesartan necessary for the trial, and patient concern about kidney function. CMR, cardiac magnetic resonance imaging.
Figure 2.
Figure 2.
Change in left ventricular mass and left ventricular mass index in patients treated with spironolactone and chlorthalidone. On intention-to-treat analysis, there was no significant difference in either drug for change in left ventricular mass (P=0.08) or left ventricular mass indexed to BSA (P=0.19) using a linear regression model adjusted for minimization variables and baseline left ventricular mass. LV, left ventricular.
Figure 3.
Figure 3.
Changes in office systolic and diastolic BP over follow-up. Change in systolic BP (A) and diastolic BP (B) associated with spironolactone (solid line) and chlorthalidone (dashed line) from initiation to end of treatment at week 40, followed by reassessment 4 weeks after cessation of the trial drug. Data are mean and 95% confidence interval.
Figure 4.
Figure 4.
Change in left ventricular mass and 24-hour ambulatory systolic BP after 40 weeks of treatment with spironolactone or chlorthalidone.
See this image and copyright information in PMC

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