Among patients with chronic kidney disease and poorly controlled hypertension, can chlorthalidone therapy improve blood-pressure control?

Comment by InpharmD Researcher

Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. However, 41% of the patients in the chlorthalidone group experienced acute kidney injury as an adverse effect, as compared to 13% in the placebo group. There was also more dizziness, hyperuricemia, hyperglycemia, hypomagnesemia and hyponatremia in the chlorthalidone group as compared to placebo. While chlorthalidone may be slightly superior to placebo for blood pressure control, higher electrolyte abnormalities may dissuade providers from using this treatment for patients.
Background

The 2020 International Society of Hypertension Global Hypertension Practice Guidelines defines high blood pressure as systolic blood pressure (SBP) ≥140 mm Hg and/or a diastolic blood pressure (DBP) ≥90 mm Hg. The following is recommended:
-Consider monotherapy in low risk grade 1 hypertension or in very old (greater than or equal to 80 years of age) or frailer patients.
-Consider an Angiotensin-converting enzyme (ACE) inhibitor or Angiotensin receptor blocker (ARB) and a thiazide-like diuretic in post-stroke, very elderly, incipient heart failure, or calcium channel blocker (CCB) intolerance.
-Consider an ACE-inhibitor or an ARB and a Dihydropyridine calcium channel blockers (DHP-CCB) OR a DHP-CCB and thiazide-like diuretic in black patients.
-Caution with spironolactone or other potassium-sparing diuretics when estimated GFR<45 mL/min/1.73m^2 OR K+ >4.5 mmol/L.

For patients with hypertension and Chronic Kidney Disease (CKD), the guideline recommends that blood pressure should be lowered if ≥140/90 mmHg and treated to a target <130/80 mmHg (<140/80 in elderly patients). RAS-inhibitors are first-line drugs as they reduce albuminuria in addition to blood pressure control. CCBs and diuretics (loop-diuretics if eGFR <30 ml/min/1.73m^2) can be added if needed, and eGFR, microalbuminuria and blood electrolytes should be monitored. [1]

The 2018 AHA/ACC Hypertension Guideline Update states that to prevent and treat hypertension, blood pressure should first
be categorized as normal (less than 120 mm Hg systolic and less than 80 mm Hg diastolic), elevated (120 to 129 mm Hg systolic and less than 80 mm Hg diastolic), stage 1 hypertension (130 to139 mm Hg systolic or 80 to 89 mm Hg diastolic), or stage 2 hypertension (at least 140 mm Hg systolic or at least 90 mm Hg diastolic). A target blood pressure of less than 130/80 mm Hg is recommended for adults with confirmed hypertension and cardiovascular disease (CVD) or a 10-year atherosclerotic CVD risk of 10% or more. A target of less than 130/80 mm Hg may be reasonable for adults with confirmed hypertension but no additional markers of increased CVD risk. The blood pressure target for adults with hypertension and CKD should be less than 130/80 mm Hg.

First-line agents include thiazide diuretics, CCB's, and ACE-inhibitors or ARBs. Initiation of blood pressure-lowering
therapy with two first-line agents of different classes (as separate agents or in a fixed-dose combination) is recommended for adults with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target. Therapy with a single agent is reasonable in adults with stage 1 hypertension and target blood pressure less than 130/80 mm Hg. [2]

According to the JNC 8 Guidelines for the Management of Hypertension in Adults (2014), persons 18 years or older with CKD or diabetes mellitus, the treatment threshold should be 140/90 mm Hg and target blood pressures should be <140/90 mm Hg. Initial antihypertensive treatment should include a thiazide diuretic, calcium channel blocker, ACE inhibitor, or ARB in the general nonblack population or a thiazide diuretic or calcium channel blocker in the general black population. [3]

The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) not only endorses the use of diuretics to treat hypertension in most patients with CKD but also recommends switching from thiazide to loop diuretics when estimated GFR falls below 30 mL/min/1.73 m2. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommends that loop diuretics are particularly useful when treating edema and high blood pressure in patients with CKD stage 4–5, in addition or as an alternative to thiazide diuretics. [4]

Thiazide diuretics reduce blood pressure by causing natriuresis, thereby reducing extracellular volume, venous return, and cardiac output. In CKD, where extracellular fluid (ECF) volume is expanded and there is an impaired natriuretic response, a loop diuretic may be needed to achieve the level of diuresis required to reduce ECF volume and decrease blood pressure.

While some studies state that thiazide diuretics are not effective when the glomerular filtration rate (GFR) is below 30 ml/min/1.73 m^2, differences in potency, duration of action, and off-target effects could have blood pressure-lowering benefits in patients with moderate-to-advanced CKD. The mechanism responsible for improved blood pressure control in patients with CKD could result from a mild diuresis produced by the more potent and/or longer-acting thiazide agents, or more likely, a result of the off-target effects causing vasodilatation.

Since the 1970's, there have been 14 studies, including 5 randomized controlled trials, that have assessed the antihypertensive and diuretic effects of thiazides in CKD. Overall, it was found that thiazide-type diuretics, alone and in combination with loop agents, were effective as antihypertensive and diuretic agents in patients with advanced CKD, and the most dramatic benefit on sodium excretion and blood pressure occurred when a thiazide-type diuretic was added to a loop agent.

Studies showed that the blood pressure lowering effect of thiazide diuretics when prescribed as mono-therapy for primary hypertension did not have significant differences in the extent of blood pressure lowering among the different agents. However, there did seem to be a benefit favoring chlorthalidone when assessing 24-hour ambulatory blood pressure (ABPM) monitoring.

Studies showed that chlorthalidone was roughly three times as potent as hydrochlorothiazide (HCTZ), though at maximum clinical doses of each drug, the reductions in systolic blood pressure were similar. It was also suggested that chlorthalidone may be superior to HCTZ for regression of left ventricular hypertrophy and reduction of cardiovascular events. Head-to-head studies comparing chlorthalidone and HCTZ showed trends favoring chlorthalidone as a more effective blood pressure lowering agent, but statistical significance in this regard was not consistently demonstrated.

The most common adverse effects observed in hypertension trials include hyponatremia, hypokalemia, hypomagnesemia, hyper-uricemia, hyperlipidemia, hyperglycemia, new-onset diabetes mellitus, and stimulation of the renin–angiotensin–aldosterone system (RAAS). Patients should be closely monitored for volume depletion, hyponatremia, hypokalemia, hypercalcemia, and acute kidney injury. Although, the risk of hypokalemia may be decreased when diuretics are used in combination with ACE-inhibitors or ARBs. [4, 5, 6, 7]

References:

1. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, Wainford RD, Williams B, Schutte AE. 2020 International Society of Hypertension global hypertension practice guidelines. J Hypertens. 2020 Jun;38(6):982-1004. doi: 10.1097/HJH.0000000000002453. PMID: 32371787.

2. Armstrong C. High Blood Pressure: ACC/AHA Releases Updated Guideline. Am Fam Physician. 2018 Mar 15;97(6):413-415. PMID: 29671535.

3. Page MR. The JNC 8 hypertension guidelines: an in-depth guide. Am J Manag Care. 2014 Jan;20(1 Spec No.):E8. PMID: 25618230.

4. Sinha AD, Agarwal R. Thiazide Diuretics in Chronic Kidney Disease. Curr Hypertens Rep. 2015 Mar;17(3):13. doi: 10.1007/s11906-014-0525-x. PMID: 25749608.

5. Blowey DL. Diuretics in the treatment of hypertension. Pediatr Nephrol. 2016 Dec;31(12):2223-2233. doi: 10.1007/s00467-016-3334-4. Epub 2016 Mar 16. PMID: 26983630.

6. Neff KM, Nawarskas JJ. Hydrochlorothiazide versus chlorthalidone in the management of hypertension. Cardiol Rev. 2010 Jan-Feb;18(1):51-6. doi: 10.1097/CRD.0b013e3181c61b52. PMID: 20010338.

7. Sinha AD, Agarwal R. Thiazides are useful agents in CKD. J Am Soc Hypertens. 2016 Apr;10(4):288-9. doi: 10.1016/j.jash.2016.02.006. Epub 2016 Feb 26. PMID: 26987648.

Relevant Prescribing Information

THALITONE® (chlorthalidone) is a thiazide-like diuretic indicated for the treatment of hypertension, and as adjacent therapy for edema associated with heart failure, liver cirrhosis, and renal disease (including nephrotic syndrome). The recommended initial dose for hypertension treatment is 15 mg daily with food, and can be increased to 25 mg if needed. The recommended dose for edema is 50 mg to 100 mg daily or 100 mg on alternate days, and can be increased to a max dose of 200 mg if needed.

Contraindications for chlorthalidone include anuria and hypersensitivity. Associated warnings include hypotension and renal impairment, and it is recommended to periodically monitor serum electrolytes. The most frequently expected adverse drug reactions are hypotension, dizziness, renal dysfunction, and electrolyte abnormalities.

Chlorthalidone may reduce Lithium renal clearance, thus potentially increasing the risk of lithium toxicity.

Chlorthalidone is not recommended for pregnant or breastfeeding patients.

Chlorthalidone should be stored at 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit).

References:

THALITONE. Package Insert. Casper Pharma LLC; 2018.

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Among patients with chronic kidney disease and poorly controlled hypertension, can chlorthalidone therapy improve blood-pressure control?

Please see Table 1 for your response.


 

Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease

Design

Double-blind, randomized, placebo-controlled trial

N= 160

Study Groups

Chlorthalidone (n= 81)

Placebo (n= 79)

Inclusion Criteria

Age greater than 18 years

Calculated glomerular filtration rate (GFR) < 30 ml/min/1.73m2 but ≥15 mL/min/1.73m2. (Stage 4 CKD)

Hypertension: BP of either ≥130 systolic or ≥80 mmHg by 24-hour ambulatory BP monitoring

Treatment with at least one antihypertensive drug; either an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). If patient has contraindications to ACE or ARB, beta blocker may be used.

Exclusion Criteria

Use of thiazide or thiazide-like drugs in the previous 12 weeks

Use of furosemide >200 mg/d.

BP of either ≥160 systolic or ≥100 mmHg by 24-hour ambulatory BP monitoring

Expected to receive renal replacement therapy within the next 3 months

Myocardial infarction, heart failure hospitalization, or stroke ≤3 months prior to randomization

Pregnant or breastfeeding women or women who are planning to become pregnant or those not using a reliable form of contraception (oral contraceptives, condoms, diaphragms).

Known hypersensitivity to thiazide or sulfa drugs

Organ transplant recipient or therapy with immunosuppressive agents

Methods

Eligible patients attended nine trial visits. Four visits took place before randomization, and four visits took place after randomization. A final visit took place two weeks after the assigned regimen was discontinued.

Patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, were randomized in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo. Randomization was stratified according to previous use of loop diuretics.

The dose was doubled every 4-weeks, if patients had a home blood pressure > 135/85 mmHg. At 4-weeks, the dose was 25 mg once daily, and at 8-weeks, the dose was 50 mg once daily (max dose).

The dose was not increased if the patient had symptomatic orthostatic hypotension, hypercalcemia, moderate hypokalemia (potassium level, <3 mmol per liter), acute gout, or recent hospitalization for poorly controlled diabetes.

The assigned regimen was discontinued or decreased if a patient had a chlorthalidone or placebo induced rash, acute kidney injury, or other severe adverse effects. Patients were withdrawn from the trial if their blood pressure exceeded 170/109 mm Hg and remained at >180/110 mm Hg one week after dose was increased. 

Duration

Trial Period: 12 weeks

Outcome Measures

Primary Outcome:

Change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks

Secondary Outcomes:

Change from baseline to 12 weeks in; urinary albumin-to-creatinine ratio, NT-proBNP level, plasma renin and aldosterone levels, and total body volume

Baseline characteristics

Characteristic

Chlorthalidone (N= 81)

Placebo (N= 79)

Age– yr

66.2+10.8

66.7+10.8

Male – no. (%)

62 (77)

62 (78)

Race – no. (%):

White

46 (57)

47 (59)

Black

32 (40)

32 (41)

Asian

2 (2)

0

Hispanic

1 (1)

0

Cause of chronic kidney disease – no. (%):

Diabetes

42 (52)

42 (53)

Hypertension

26 (32)

26 (33)

Glomerulonephritis

3 (4)

5 (6)

Obstructive uropathy

3 (4)

2 (3)

Polycystic kidney disease

1 (1)

1 (1)

Other

6 (7)

3 (4)

Current smoking – no. (%)

21 (26)

19 (24)

Body-mass index

33.0+7.0

32.0+7.4

Systolic blood pressure– mm Hg

141.2+15.1

138.7+16.0

Diastolic blood pressure– mm Hg

69.2+12.3

67.9+13.9

Pulse rate – beats/min

66.5+11.7

64.3+11.1

Median spot urinary albumin-to-creatinine ratio (IQR)

862 (187–2274)

812 (128–2022)

Urinary albumin-to-creatinine ratio category — no. (%):

<30

5 (6)

9 (11)

30 to <300

19 (23)

19 (24)

>300

56 (69)

51 (65)

Estimated GFR — ml/min/1.73 m2

23.5+4.2

22.8+4.2

Median NT-proBNP (IQR) — pg/ml

545 (189–1342)

636 (274–1601)

Median plasma renin (IQR) — pg/ml

2276 (1160–4702)

2611 (1198–4870)

Median plasma aldosterone (IQR) — pg/ml

313 (181–519)

321 (189–499)

Median urine sodium excretion (IQR) — mmol/24 hr:

115 (82–142)

96 (77–129)

Results

Primary Outcome:

 

Chlorthalidone

Placebo

Between-group difference

95% CI

P-value

 

Adjusted change in 24-hours from baseline to 12 weeks

95% CI

Adjusted change in 24-hours from baseline to 12 weeks

95% CI

 

Systolic Blood Pressure

-11.0 mm Hg

-13.9 to -8.1

-0.5 mm Hg

-3.5 to 2.5

-10.5 mm Hg

-14.6 to -6.5

P< 0.001

Diastolic Blood Pressure

-4.9 mm Hg

-1.0 mm Hg

-3.9 mm Hg

-6.3 to -1.5

 

Secondary Outcomes:

Percent change from baseline to 12 weeks:

 

Placebo (95% CI)

Chlorthalidone (95% CI)

Percentage Point Difference (95% CI)

Urinary albumin-to-creatinine ratio

 

-4 (-18 to -12)

-52 (-59 to -43)

-50 (-60 to -37)

NT-proBNP level

 

-11 (-23 to 2)

-30 (-39 to -19)

-21 (-35 to -4)

Plasma renin levels

15 (6 to 25)

64 (50 to 78)

42 (26 to 60)

Plasma aldosterone levels

8 (-8 to -27)

52 (28 to 79)

41 (12 to 77)

Total body volume

0.3 (-0.3 to -0.8)

-2 (-2.6 to -1.5)

-2.3 (-3 to -1.5)

 

Safety

 

 

 

Chlorthalidone (N= 79)

 

Placebo (N= 81)

 

No. of patients with event (%)

No. of events

No. of patients with event (%)

No. of events

Adverse events:

Total

74 (91)

330

68 (86)

219

Infection

6 (7)

6

10 (13)

10

Cardiovascular event

2 (2)

2

3 (4)

3

Other

42 (52)

57

39 (49)

64

Hypokalemia

8 (10)

10

0

0

Hypomagnesemia

19 (23)

35

13 (16)

26

Hyponatremia

9 (11)

12

6 (8)

6

Hypocalcemia

1(1)

1

1(1)

3

Hypercalcemia

2 (2)

3

2 (3)

3

Hyperglycemia

13 (16)

18

4 (5)

5

Hyperuricemia

16 (20)

32

7 (9)

9

Hyperkalemia

5 (6)

5

7 (9)

8

Hypernatremia

0

0

1(1)

1

Acute gout

2 (2)

2

3 (4)

3

Syncope

2 (2)

2

1 (1)

1

Orthostati hypotension

8 (10)

12

5 (6)

8

Dizziness

20 (25)

33

13 (16)

24

Asymptomatic orthosatic hypertension

21 (26)

39

18 (23)

33

Acute kidney injury

33 (41)

61

10 (13)

12

Serious Adverse Events:

Infection

2 (2)

3

1 (1)

1

Cardiovascular event

3 (4)

3

5 (6)

7

Renal event

1 (1)

1

1 (1)

1

Event of interest

3 (4)

4

0

0

Other

3 (4)

3

5 (6)

6

Total

8 (10)

14

11 (14)

15

 

Study Author Conclusions

Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo.

InpharmDTM Researcher Critique

Chlorthalidone therapy showed effective blood pressure reduction. However, the sample was limited, and further studies need to be done in more diverse and larger populations. 

Additionally, while the results were positive, the clinical relevance may differ depending on practice and patient. While chlorthalidone effectively reduced blood pressure, it was also associated with more acute kidney disease, dizziness, hyperuricemia, hyperglycemia, hypomagnesemia and hyponatremia, as compared to placebo. Thus, it may not be the best choice of treatment for some patients. 

 

 

References:

Agarwal R, Sinha AD, Cramer AE, Balmes-Fenwick M, Dickinson JH, Ouyang F, Tu W. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease. N Engl J Med. 2021 Nov 5. doi: 10.1056/NEJMoa2110730. Epub ahead of print. PMID: 34739197.