The thiazide-like diuretic chlorthalidone as an alternative evidence-based therapy for resistant hypertension in patients with stage 4 chronic kidney disease

KEYWORDS:

• Chlorthalidone
• CKD
• resistant hypertension
• randomized controlled trials
• spironolactone

1. Definition and epidemiology of resistant hypertension in chronic kidney disease

Resistant hypertension is defined as the failure to achieve adequate blood pressure (BP) control, despite optimal treatment with maximum or maximally-tolerated doses of 3 antihypertensive medications from different categories, inclusive of a diuretic [1]. Those with controlled BP on treatment with ≥ 4 antihypertensives also meet the diagnostic criteria of resistant hypertension [1].

This clinical condition is not infrequent in the general population of treated patients with hypertension. In a global meta-analysis of 91 studies incorporating data from a pooled sample of 3.2 million patients, the prevalence of apparent-treatment resistant hypertension (aTRH) in the general population was estimated to be 14.7% [95% confidence interval (CI): 13.1%-16.3%] [2]. In contrast, among patients with chronic kidney disease (CKD), the burden of aTRH is 2-fold to 3-fold greater [3]. For example, among 3,367 drug-treated hypertensives with stage 2–4 CKD participating in the CRIC study, the prevalence of aTRH was 40.4% [4]. As compared to those without aTRH, patients with aTRH had 38% higher risk for cardiovascular morbidity, 28% greater risk for faster progression of CKD and 24% increased risk for all-cause mortality [4]. Although resistant hypertension is highly prevalent and is prognostically associated with excess risk for adverse clinical outcomes, few therapeutic options are currently available to improve BP control, particularly in patients with more advanced CKD [5–8].

In this article, we discuss the role of the thiazide-like diuretic chlorthalidone as an alternative evidence-based therapy for patients with advanced CKD and poorly controlled hypertension.

2. Spironolactone and the barrier of hyperkalemia in advanced CKD

The steroidal mineralocorticoid-receptor-antagonist (MRA) spironolactone is recommended by guidelines as the preferred fourth-line agent for patients with inadequately controlled BP, despite combination therapy with maximally-tolerated doses of a renin-angiotensin-system blocker, a dihydropyridine calcium-channel-blocker and a diuretic [6]. Earlier interventional studies suggested that the addition of low-dose spironolactone to a multi-drug antihypertensive regimen was accompanied by a clinically meaningful reduction in office BP in patients with resistant hypertension [9]. This potent effect of spironolactone was confirmed by the PATHWAY-2 trial [10]. In PATHWAY-2, the average reduction in home systolic BP provoked by spironolactone over 12 weeks of follow-up was superior to placebo and superior to active-treatment either with doxazosin or with bisoprolol [10]. As PATHWAY-2 included predominantly hypertensive patients with well-preserved kidney function (mean eGFR at baseline: 91.1 ml/min/1.73 m²), elevations in serum potassium levels in response to spironolactone treatment were not a significant safety concern over the course of the trial [10]. However, the risk of hyperkalemia progressively increases, as the levels of estimated-glomerular-filtration-rate (eGFR) decline [11,12]. Taking into consideration the associated risk of hyperkalemia, the 2018 and the updated 2023 guidelines of the European Society of Hypertension (ESH) discourage the use of spironolactone for the management of resistant hypertension when the pre-treatment levels of serum potassium are > 4.5 mEq/l or when the levels of eGFR are <45 ml/min/1.73 m² [6,8].

In the AMBER trial [13], relative to placebo, patiromer, a potassium-binding polymer, mitigated the risk of hyperkalemia and enabled more patients with uncontrolled resistant hypertension and moderate-to-advanced CKD (eGFR 25–45 ml/min/1.73 m²) to maintain on spironolactone treatment. Notably, even with the concomitant administration of patiromer, approximately one third of patients who received add-on therapy with spironolactone developed hyperkalemia (defined as a serum potassium ≥ 5.5 mEq/l) over 12 weeks of therapy; in placebo-treated patients, the incidence of hyperkalemia with spironolactone was substantially higher (~60%) [13]. Newer agents, such as the non-steroidal MRA ocedurenone, are currently under clinical development for the effective management of hypertension in moderate-to-advanced CKD, offering promise for a more favorable side-effect profile [14]. However, the long-term safety and BP-lowering efficacy of ocedurenone remains to be determined in ongoing randomized trials. In anticipation of the approval of newer antihypertensives, recent clinical-trial evidence suggests that currently available antihypertensives are actually effective in lowering ambulatory BP in patients with advanced CKD and poorly controlled hypertension.

3. Safety and BP-lowering efficacy of chlorthalidone ― the CLICK trial

The vast majority of guidelines released over the past 2 decades have consistently provided the recommendation that when the levels of eGFR fall below the threshold of 30 ml/min/1.73 m², diuretic therapy in patients with hypertension should be appropriately adjusted [5,7,8]. There was an established belief that hydrochlorothiazide loses its potency when the eGFR is <45 ml/min/1.73 m², whereas the thiazide-like diuretic chlorthalidone retains its action till the eGFR threshold of 30 ml/min/1.73 m². Therefore these agents should be replaced by a more potent loop diuretic in people with stage 4 CKD. This ‘status quo’ has been reappraised after the publication of the 2023 ESH guidelines [6], in which the thiazide-like diuretic chlorthalidone is now recommended as the preferred fourth-line agent for patients with resistant hypertension and an eGFR ranging from 30 down to 15 ml/min/1.73 m². This important shift in practice has been based on strong evidence from the CLICK trial [15] (Table 1).

Table 1. Main results of the chlorthalidone in chronic kidney disease (CLICK) trial [15].

Study design	Double-blind, randomized, placebo-controlled trial
Patients’ characteristics	Stage 4 CKD and poorly controlled hypertension
N	160
Mean eGFR at baseline	23.2 ± 4.2 ml/min/1.73 m^2
Administered number of BP-lowering medications	3.4 ± 1.4
Proportion of patients on loop diuretics	96/160, 60%
Placebo-subtracted CFB in 24-hour systolic BP	−10.5 mmHg (95% CI: −14.6 to −6.4)
Placebo-subtracted CFB in 24-hour diastolic BP	−3.9 mmHg (95% CI: −6.3 to −1.5)
Placebo-subtracted CFB in UACR	−50% (95% CI: −60% to −37%)
Commonly reported adverse events	Hyponatremia, hypokalemia, hyperuricemia, hyperglycemia, dizziness, orthostatic hypotension, reversible increases in the levels of serum creatinine

Abbreviations: BP= blood pressure; CI= confidence interval; CFB= change from baseline; CKD= chronic kidney disease; eGFR= estimated glomerular filtration rate; UACR= urinary albumin-to-creatinine ratio.

In detail, CLICK randomized 160 patients with stage 4 CKD (eGFR <30 but ≥15 ml/min/1.73 m²) and uncontrolled hypertension, as confirmed by the reference-standard method of 24-hour ambulatory BP monitoring, to receive double-blind treatment either with chlorthalidone or with placebo [16]. Chlorthalidone was administered at an initial dose of 12.5 mg once daily, with an as needed intensification of therapy at 4-week intervals up to a maximum dose of 50 mg once daily [16]. Notably, this maximum dose administered in CLICK is 2-fold higher than the daily dose recommended for the treatment of essential hypertension. Over 12 weeks of follow-up, the placebo-subtracted change in 24-hour ambulatory systolic BP with chlorthalidone was −10.5 mmHg (95% CI: −14.6 to −6.4). The corresponding mean difference between the chlorthalidone and placebo groups in the change from baseline of 24-hour ambulatory diastolic BP was −3.9 mmHg (95% CI: −6.3 to −1.5) [15]. In chlorthalidone-treated patients, over the first 4 weeks of follow-up, significant reductions were evident in body weight, body volume, levels of N-terminal pro-B-type natriuretic peptide in parallel with elevations in the levels of plasma renin and aldosterone, evidence supporting the notion that changes in effective arterial blood volume was the most likely mechanism to explain the potent BP-lowering effect of chlorthalidone. Furthermore, the ambulatory BP reduction was paralleled with a remarkable improvement in albuminuria, preliminary data supporting a potential cardiorenal protective action of chlorthalidone. Between baseline and 12 weeks of follow-up, the urinary albumin-to-creatinine ratio was by 50% lower in chlorthalidone-treated than in placebo-treated patients (95% CI: 37% to 60%) [15]. With respect to the safety profile of chlorthalidone, several adverse events, such as hypokalemia, hyperglycemia, hyperuricemia, dizziness, orthostatic hypotension and reversible elevations in the levels of serum creatinine, occurred more frequently in the active-treatment group than in the placebo group [15].

Of the 160 patients who underwent randomization, 113 patients (70.6%) had 24-hour ambulatory BP ≥ 130/80 mmHg despite the use of ≥ 3 antihypertensives [17]. In this prespecified subgroup of patients, relative to placebo, chlorthalidone provoked an average change of −13.9 mmHg (95% CI: −19.4 to −8.8) in 24-hour ambulatory systolic BP and an average change of −5.8 mmHg (95% CI: −9.0 to −2.6) in 24-hour ambulatory diastolic BP [17]. The albuminuria-lowering effect of chlorthalidone was similar in magnitude as in the overall study population; the mean difference in the change from baseline of urinary albumin-to-creatinine ratio between chlorthalidone and placebo groups was −54% (95% CI: −65% to −40%) [17]. These post-hoc data are supporting the effectiveness of chlorthalidone for the treatment of resistant hypertension in patients with advanced CKD.

Finally, a subgroup of 96 out of 160 patients (60%) was receiving background therapy with a loop diuretic [15]. The placebo-subtracted reduction in 24-hour ambulatory BP provoked by chlorthalidone was similar in magnitude in loop diuretic users and non-users. Although the BP-lowering efficacy was unaffected, the safety profile of chlorthalidone was substantially modified by background treatment with loop diuretics. Among patients who were not receiving loop diuretics at randomization, the odds ratio for a reversible elevation in the levels of serum creatinine ≥ 25% was 1.9 (95% CI: 0.4 to 10.3) [15]. In sharp contrast, among loop diuretic users, the odds ratio for this adverse event was 9.2 (95% CI: 3.0 to 31.3) [15].

These subgroup analyses indicate that the administration of chlorthalidone at an even lower starting dose than that used in CLICK might be a reasonable approach to prevent the occurrence of adverse events seen with chlorthalidone, mainly in patients who are receiving concomitant treatment with loop diuretics [18].

A notable advantage of chlorthalidone over spironolactone is the fact that hyperkalemia is not a safety concern for its long-term use. However, the levels of serum potassium should be closely monitored, because the incidence of hypokalemia was significantly higher in chlorthalidone-treated (10%) than in placebo-treated (0%) patients over the course of the CLICK trial [15]. Once again, the risk of hypokalemia may be substantially higher in patients receiving background therapy with a loop diuretic.

4. Expert opinion

Despite the fact that the prevalence of resistant hypertension is 2 to 3 times greater in patients with advanced CKD than in the general population [3], the currently available therapies to improve BP control in this subgroup of high-risk patients are few. Spironolactone is recommended by guidelines as the standard-of-care treatment for resistant hypertension [6–8], but the use of this steroidal MRA in patients with eGFR <45 ml/min/1.73 m² is commonly restricted due to the associated risk of hyperkalemia [12]. Evidence from the recently published CLICK trial indicate that chlorthalidone, a thiazide-like diuretic, is effective in reducing the levels of ambulatory BP in patients with stage 4 CKD and inadequately controlled hypertension [15,17]. The BP-lowering effect of chlorthalidone is also accompanied by a clinically meaningful improvement in albuminuria, preliminary evidence suggesting that chlorthalidone is possibly renoprotective and cardioprotective [15,17]. Based on these important clinical-trial data, the 2023 ESH guidelines have included chlorthalidone in the therapeutic algorithm of resistant hypertension in patients with advanced CKD [6]. However, the use of this agent in everyday clinical practice should be sensible, necessitating the close monitoring of BP, serum electrolytes and kidney function for the prevention of adverse events that commonly occur in chlorthalidone-treated patients. The risk for adverse events is even higher when chlorthalidone is administered in combination with a loop diuretic. In such patients, it is advisable to administer chlorthalidone at en even lower starting dose than the initial dose that was used in CLICK (i.e. 6.25 mg once daily or 12.5 mg every other day) [18].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Literature search: PI Georgianos, V Vaios, I Kontogiorgos; Writing the initial draft of the manuscript: PI Georgianos, V Vaios, I Kontogiorgos; Reviewing and editing the manuscript: M Divani, V Liakopoulos; Supervision: V Liakopoulos

Additional information

Funding

This paper was not funded.