From the Guidelines
Chlorthalidone is generally more effective than hydrochlorothiazide for blood pressure control, despite potential metabolic side effects, and should be considered as the first-line treatment for hypertension due to its superior efficacy in reducing cardiovascular events, as demonstrated in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 1.
Key Differences Between Chlorthalidone and Hydrochlorothiazide
- Chlorthalidone has a longer half-life (40-60 hours) compared to hydrochlorothiazide (8-15 hours), providing more consistent 24-hour blood pressure reduction and superior nighttime blood pressure control.
- Clinical studies have shown that chlorthalidone reduces cardiovascular events more effectively than hydrochlorothiazide at standard doses (12.5-25 mg chlorthalidone versus 25-50 mg hydrochlorothiazide daily) 1.
- Chlorthalidone may cause more metabolic side effects, including greater reductions in potassium levels, more glucose abnormalities, and higher uric acid levels, as reported in a meta-analysis of 25 RCTs involving chlorthalidone and hydrochlorothiazide 1.
Treatment Recommendations
- When initiating treatment, chlorthalidone should be started at 12.5 mg daily and can be increased to 25 mg if needed, while hydrochlorothiazide typically starts at 12.5-25 mg daily.
- Both medications should be taken in the morning to prevent nighttime urination, and regular monitoring of electrolytes, particularly potassium, is essential with either medication.
- The European guidelines on cardiovascular disease prevention in clinical practice recommend thiazide diuretics, such as chlorthalidone, as a suitable option for initiation and maintenance of antihypertensive treatment, either as monotherapy or in combination 1.
Considerations for Specific Patient Populations
- In patients with coronary heart disease, the INVEST study reported similar incidences of coronary and cardiovascular events by treatment with verapamil or atenolol, while the ALLHAT trial showed similar incidences of coronary and cardiovascular events by treatment with chlorthalidone, lisinopril, or amlodipine 1.
- In patients with heart failure, treatment can make use of thiazide and loop diuretics, as well as beta-blockers, antialdosterone drugs, ACE inhibitors, and angiotensin receptor antagonists administered on top of diuretic therapy 1.
From the Research
Effectiveness of Hydrochlorothiazide and Chlorthalidone
- Both hydrochlorothiazide (HCTZ) and chlorthalidone are effective in lowering blood pressure, with some studies suggesting a trend towards chlorthalidone being more effective 2.
- A study published in 2020 found that chlorthalidone was not associated with significant cardiovascular benefits compared to HCTZ, while its use was associated with a greater risk of renal and electrolyte abnormalities 3.
- Another study published in 2022 found that there was little difference in the occurrence of primary-outcome events between the chlorthalidone group and the HCTZ group, with a hazard ratio of 1.04 (95% confidence interval, 0.94 to 1.16; P = 0.45) 4.
Safety Outcomes
- Chlorthalidone has been associated with a higher risk of hypokalemia, hyponatremia, acute renal failure, chronic kidney disease, and type 2 diabetes mellitus compared to HCTZ 3.
- However, chlorthalidone was also associated with a lower risk of diagnosed abnormal weight gain compared to HCTZ 3.
- The incidence of hypokalemia was higher in the chlorthalidone group than in the HCTZ group (6.0% vs. 4.4%, P<0.001) in a study published in 2022 4.
Clinical Implications
- The available evidence supports both HCTZ and chlorthalidone as safe and effective drugs for treating hypertension, although the results are not conclusive 2.
- The choice between HCTZ and chlorthalidone may depend on individual patient factors, such as the presence of certain comorbidities or the risk of adverse effects 3, 5.
- Further study is warranted to fully understand the relative benefits and risks of HCTZ and chlorthalidone in the treatment of hypertension 3, 4.