Chlorthalidone Versus Hydrochlorothiazide for Hypertension

Hypertension (high blood pressure) is one of the most common medical disorders in the U.S., affecting more than a quarter of all adults and two-thirds of adults age 60 or older.[1] It is a major risk factor for the development of heart attacks, strokes, kidney disease and circulation disorders. Approximately three-quarters of adults with hypertension take medication to lower their blood pressure.[2]

For most patients whose blood pressure cannot be controlled through lifestyle interventions — such as changing one’s diet (decreasing sodium and fat intake, increasing potassium and fiber intake), exercising regularly, losing weight, restricting alcohol consumption and quitting smoking[3],[4] — a thiazide diuretic (water pill) should be the initial drug of choice. Two of the most frequently used thiazide diuretics in patients with high blood pressure are hydrochlorothiazide (ORETIC, MICROZIDE) and chlorthalidone (THALITONE).

Previous research has not definitively proved whether one of these drugs is better than the other at treating hypertension. A recent Annals of Internal Medicine (Annals) study provides new evidence suggesting that though both drugs are equally effective in preventing the serious complications of hypertension in adults older than 65, chlorthalidone appears more likely to cause hypokalemia (low blood potassium levels) and hyponatremia (low blood sodium levels) severe enough to require hospitalization.[5]

Comparing the drugs

The exact mechanism by which hydrochlorothiazide and chlorthalidone lower blood pressure is unknown.[6],[7] Both cause the kidney to excrete more sodium and water into the urine, which may reduce blood pressure by decreasing the amount of salt and water in the body. These drugs also may lower blood pressure by causing the blood vessels that regulate blood pressure to dilate or relax.[8]

Though both drugs are eliminated from the body by the kidneys, chlorthalidone is cleared four to 10 times more slowly than hydrochlorothiazide,[9],[10] making chlorthalidone a much longer-acting diuretic. Despite the significant difference in their rates of metabolism, both drugs are usually administered once daily. The usual recommended daily dose for hydrochlorothiazide is 12.5 to 50 milligrams (mg), and the usual dose for chlorthalidone is 12.5 to 25 mg.[11]

Like all thiazide diuretics, hydrochlorothiazide and chlorthalidone both can cause low blood levels of potassium and sodium by increasing the losses of potassium, sodium and water in the urine. Extreme decreases in the levels of these blood electrolytes (salts) can lead to severe, life-threatening adverse events. Rare side effects that can occur with hydrochlorothiazide, but not chlorthalidone, are acute myopia (near-sightedness) and a type of glaucoma called acute angle-closure glaucoma, which can lead to blindness if not promptly treated.[12]

Study overview[13]

To better understand the relative advantages and disadvantages of hydrochlorothiazide and chlorthalidone, researchers in Canada conducted an observational study that was published on March 19, 2013. The researchers used computerized medical, pharmacy and other records for adult residents of Ontario, Canada, older than age 65. The province of Ontario has a diverse population of more than 13 million people, all of whom have coverage for physician and hospital health care services. From the computerized records, the researchers identified a group of more than 1.1 million patients who were newly treated with hydrochlorothiazide or chlorthalidone for uncomplicated hypertension between January 1993 and March 2010.

The researchers excluded patients who had been prescribed any thiazide diuretic during the one-year period prior to starting hydrochlorothiazide or chlorthalidone. To maximize the chances that the study population was limited to patients with uncomplicated hypertension, they also excluded patients who had previously been hospitalized for heart attack, congestive heart failure or stroke during the year prior to starting either of the two drugs of interest. After applying these exclusion criteria, they were left with 643,529 patients who had received hydrochlorothiazide and 11,389 who had received chlorthalidone.

The researchers then attempted to compare each chlorthalidone-treated patient with at least one and, whenever possible, two hydrochlorothiazide-treated patients matched for age, sex, the calendar year the diuretic drug was initiated and use of other nonthiazide antihypertensive drugs.

Following application of all exclusion and matching criteria, the final study cohort included 10,384 patients newly treated with chlorthalidone and 19,489 patients newly treated with hydrochlorothiazide. These patients were followed for a maximum of five years.

To compare the effectiveness of the two study drugs, the researchers determined whether the patients in the cohort experienced any of the following events: death or hospitalization for heart attack, heart failure or ischemic stroke while on these drugs. To measure problems with the drugs’ safety, the researchers examined whether the patients in the cohort were hospitalized for low blood potassium or sodium levels, as well as whether they were hospitalized for any reason.

Study results[14]

The average age of the appropriately matched patients in each group was 73, and 59 percent were women. The average length of follow-up was 255 days in the chlorthalidone patients compared to 398 days in the hydrochlorothiazide patients. For the matched cohorts, the initially prescribed doses of chlorthalidone were 12.5, 25 and 50 mg in 11, 70 and 10 percent of patients, respectively. In contrast, 67, 24 and 5 percent, respectively, of the hydrochlorothiazide patients were initially prescribed these same three doses. (The significantly higher frequency of initial prescriptions for chlorthalidone at doses of 25 and 50 mg versus those for hydrochlorothiazide was somewhat surprising given that chlorthalidone is known to be a longer-acting and more potent diuretic.)

When assessing the relative effectiveness of the two diuretics — after adjusting for multiple baseline characteristics, including other medical conditions and use of other prescription drugs — the researchers found no statistically significant difference between the two groups for the combined endpoint of death or hospitalization for heart attack, heart failure or ischemic stroke. These events The researchers likewise found no significant differences between the two study groups when they looked separately at the rates of death, heart attack, heart failure or ischemic stroke.

These events occurred at combined rates of 3.2 events per 100 patients per year of follow-up in the chlorthalidone group and 3.4 events per 100 patients per year of follow-up in the hydrochlorothiazide group, not statistically significantly different. The researchers likewise found no significant differences between the two study groups when they looked separately at the rates of death, heart attack, heart failure or ischemic stroke.

With respect to safety outcomes, the researchers did find important statistically significant differences between the two study groups. Hospitalization for low blood potassium levels occurred at rates of 0.69 events per 100 patients per year in the chlorthalidone group and 0.27 events per 100 patients per year in the hydrochlorothiazide group. After again adjusting for multiple baseline patient characteristics between the two study groups, the chlorthalidone-treated patients were approximately three times more likely to be hospitalized for low blood potassium levels than the hydrochlorothiazide-treated patients.

Furthermore, hospitalization for low blood sodium levels occurred at rates of 0.69 events per 100 patients per year in the chlorthalidone group and 0.49 events per 100 patients per year in the hydrochlorothiazide group. After adjustment for baseline characteristics, the chlorthalidone-treated patients were approximately 1.7 times more likely to be hospitalized for low blood sodium levels in comparison to hydrochlorothiazide-treated patients.

Prior research

No large randomized, controlled trial has been conducted comparing chlorthalidone and hydrochlorothiazide. One nonrandomized, retrospective cohort study suggested that men with hypertension treated with chlorthalidone were less likely to have adverse cardiovascular events than those treated with hydrochlorothiazide.[15] However, as the authors of the Annals study pointed out, this earlier study did not control for important baseline differences between patients taking each of these two diuretics, which could have biased the study results. The earlier study also did not include women, and the patient population was much younger (ages 35 to 57) when treatment for hypertension was initiated. Finally, this prior study did not assess rates of hospitalization for low potassium or sodium levels.

Two published studies, using a technique called meta-analysis, compared the results of clinical trials testing chlorthalidone for treatment of hypertension to similar but separate clinical trials testing hydrochlorothiazide. One meta-analysis study found no significant difference in cardiovascular outcomes for the two drugs,[16] whereas the other study suggested that chlorthalidone appeared to be superior to hydrochlorothiazide with respect to cardiovascular outcomes.[17] Neither study reported data on low blood potassium or sodium levels.

In discussing the results of their Annals study, the researchers noted that some other recent studies have shown that chlorthalidone is more potent than hydrochlorothiazide in both reducing blood pressure and increasing excretion of potassium by the kidneys.[18],[19] For example, one study suggested that chlorthalidone may be four times more potent than hydrochlorothiazide in lowering blood pressure and blood potassium levels.[20]

Given that chlorthalidone is both longer acting and more potent than hydrochlorothiazide, it is certainly biologically plausible that chlorthalidone would be more likely to cause more frequent and more severe episodes of low blood potassium and sodium levels in comparison to hydrochlorothiazide.

What You Can Do

Both hydrochlorothiazide and chlorthalidone overall are excellent, safe and effective choices for initial treatment of uncomplicated hypertension in older adults.

If you are starting either drug for the first time, the initial dose in most cases should be 12.5 mg. If your blood pressure is not adequately controlled with the 12.5 mg dose, it would be reasonable for your health care provider to increase the dose to 25 mg. You should not — in most cases — be taking more than 50 mg per day of either drug.

After initiating use or increasing the dose of either hydrochlorothiazide or chlorthalidone, you should ensure that you have follow-up blood tests within one to two months to check your blood potassium and sodium levels.

If you are being treated with chlorthalidone and experience problems with either low potassium or low sodium blood levels, you should discuss with your doctor either decreasing the dose or switching to hydrochlorothiazide. Potassium supplements also may be appropriate when taking either diuretic.

References

[1] Yoon SS, Burt V, Louis T, Carroll MD. Hypertension Among Adults in the United States, 2009–2010. Centers for Disease Control and Prevention: National Center for Health Statistics Data Brief. No. 107. October 2012. http://www.cdc.gov/nchs/data/databriefs/db107.pdf. Accessed May 11, 2012.

[2] Ibid.

[3] Worst Pills.org monograph on hypertension. /chapters/view/41. Accessed May 11, 2013.

[4] Chobanian AV, Bakris GL, Black HR, Cushman WC, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42(6):1206-1252.

[5] Dhalla IA, Gomes T, Yao Z, Nagge J, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: A population-based cohort study. Ann Intern Med. 2013:158(6):447-455.

[6] Watson Pharma, Inc. Drug label for Microzide - hydrochlorothiazide. Revised October 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=afbefaff-97c4-4f84-b989-1595f882a885. Accessed May 11, 2013.

[7] Monarch Pharmaceuticals, Inc. Drug label for Thalitone – chlorthalidone. January 2004. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e2eb7dad-3ea3-439c-dcbb-d1d61aa49dfc. Accessed May 11, 2013.

[8] Watson Pharma, Inc. Drug label for Microzide - hydrochlorothiazide. Revised October 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=afbefaff-97c4-4f84-b989-1595f882a885. Accessed May 11, 2013.

[9] Ibid.

[10] Monarch Pharmaceuticals, Inc. Drug label for Thalitone – chlorthalidone. January 2004. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e2eb7dad-3ea3-439c-dcbb-d1d61aa49dfc. Accessed May 11, 2013.

[11] Chobanian AV, Bakris GL, Black HR, Cushman WC, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252.

[12] Watson Pharma, Inc. Drug label for Microzide - hydrochlorothiazide. Revised October 2011. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=afbefaff-97c4-4f84-b989-1595f882a885. Accessed May 11, 2013.

[13] Dhalla IA, Gomes T, Yao Z, Nagge J, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: A population-based cohort study. Ann Intern Med. 2013:158(6):447-455.

[14] Ibid.

[15] Dorsch MP, Gillespie BW, Erickson SR, et al. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 201;57(4):689-694.

[16] Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic therapies [Letter]. JAMA. 2004;292(1):43-44.

[17] Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension. 2012;59(6):1110-1117.

[18] Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bedroflumethiazide on blood pressure, serum potassium, and urate. Hypertension. 2012; 59(6):1104-1109.

[19] Ernst ME, Carter BL, Zheng S, Grimm RH. Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am J Hyperten. 2010;23(4):440-446.

[20] Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bedroflumethiazide on blood pressure, serum potassium, and urate. Hypertension. 2012; 59(6):1104-1109.