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Low-dose chlorthalidone superior to low-dose hydrochlorothiazide for sustained BP lowering
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In a new study, low-dose chlorthalidone was associated with further reductions in mean 24-hour BP compared with low-dose hydrochlorothiazide in patients with stage 1 hypertension.
Low-dose hydrochlorothiazide is the most commonly prescribed BP-lowering drug in the United States, but it appears to be a short-acting drug. Anil K. Pareek, MD, and colleagues conducted a study to compare whether low-dose chlorthalidone is a better option for reduction of 24-hour BP.
The researchers randomly assigned 54 patients with stage 1 hypertension (mean age, 45 years) to chlorthalidone 6.25 mg, hydrochlorothiazide 12.5 mg or a controlled-release version of hydrochlorothiazide 12.5 mg.
Pareek and colleagues performed 24-hour ambulatory BP monitoring on all patients at baseline, at 4 weeks and at 12 weeks.
At 4 weeks and 12 weeks, all three treatments were associated with lowering of office BP (P < .01 for all), the researchers found.
Sustained BP lowering
Chlorthalidone was associated with lowering of ambulatory systolic BP at 4 weeks (change, –6.74 mm Hg; P = .005) and 12 weeks (change, –12.11 mm Hg; P = .001), and ambulatory diastolic BP at 4 weeks (change, –5.73 mm Hg; P = .013) and 12 weeks (change, –8.74 mm Hg; P = .002). Controlled-release hydrochlorothiazide was associated with similar reductions at the same time points (P for change in systolic BP at 4 weeks = .014; P for change in systolic BP at 12 weeks = .034; P for change in diastolic BP at 4 weeks = .012; P for change in diastolic BP at 12 weeks = .014). However, the association was not similar for conventional hydrochlorothiazide (P for change in systolic BP at 4 weeks = .191; P for change in systolic BP at 12 weeks = .017; P for change in diastolic BP at 4 weeks = .217; P for change in diastolic BP at 12 weeks = .058), according to the results.
Similarly, chlorthalidone and controlled-release hydrochlorothiazide lowered ambulatory nighttime mean systolic BP and diastolic BP at 4 weeks and 12 weeks, but conventional hydrochlorothiazide did not. According to the researchers, nighttime systolic ambulatory BP was lower in the chlorthalidone group vs. the conventional hydrochlorothiazide group at 4 weeks (P = .015) and 12 weeks (P = .02).
“This discrepancy between [ambulatory BP monitoring] and office BP indicates that [hydrochlorothiazide] lowers BP appropriately during the daytime, when patients are seen on the physician’s office, but has little if any effect during the night and early morning hours,” Pareek, president of medical affairs and clinical research at Ipca Laboratories Limited in Mumbai, India, and colleagues wrote. “In contrast to conventional [hydrochlorothiazide], chlorthalidone (and [controlled-release hydrochlorothiazide]) provides smooth BP control throughout the diurnal cycle.”
Long-acting therapies beneficial
The results of this study may not be generalizable because of the small sample size and exclusion of patients aged older than 65 years, Hillel Sternlicht, MD, and George L. Bakris, MD, both from the department of medicine, American Society of Hypertension Comprehensive Hypertension Center, University of Chicago Medicine, wrote in an accompanying editorial.
George L. Bakris
However, “the clear message is that a low dose of a long-acting diuretic therapy can have a meaningful impact on the management of hypertension and on CV outcomes,” Sternlicht and Bakris, a member of the Cardiology Today Editorial Board, wrote. – by Erik Swain
Disclosure: The study was sponsored by Ipca Laboratories Limited, of which Pareek is an employee. Please see the full study for a list of the other researchers’ relevant financial disclosures. Bakris reports consulting for AbbVie, AstraZeneca, Bayer, Daiichi Sankyo, Janssen Pharmaceuticals, NxStage and Takeda and serving as principal investigator for a trial sponsored by Bayer. Sternlicht reports no relevant financial disclosures.
Perspective
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Michael A. Weber, MD
The findings of this new study add very little of value to most practitioners in the United States, and I suspect many other countries as well. These investigators have studied very low doses of the diuretics hydrochlorothiazide and chlorthalidone that are not available for prescription in the United States, thus making much of what the authors have concluded largely irrelevant.
The study’s main finding was that chlorthalidone in a dose of 6.25 mg was superior to hydrochlorothiazide 12.5 mg in reducing 24-hour ambulatory BP. But that really isn’t very helpful, since the lowest-dose tablet available in the United States for chlorthalidone is 25 mg, and hydrochlorothiazide 12.5 mg is available only in combination with other drugs.
Another thing that I didn’t think was terribly helpful about this study is that some very authoritative clinical trials by true experts in the field have already shown that chlorthalidone is more powerful and longer-acting than hydrochlorothiazide, so I’m not sure what these new data are teaching us. The fact that they have focused on low doses is really of marginal interest since most clinicians would not use these low doses unless they were part of combination treatment. If they are used as part of combination treatment rather than as single agents, the effects of diuretics can be quite different. For instance, monotherapy with hydrochlorothiazide 12.5 mg, as these investigators show, provides only a very modest reduction in BP. But when this low dose is combined with another type of drug such as an angiotensin receptor blocker or an ACE inhibitor, this low dose actually provides a useful and clinically meaningful additional BP reduction. So for these reasons, I do not find this new information very valuable, and I worry that it could even be misconstrued and have the effect of misleading prescribers into believing that low-dose hydrochlorothiazide is not valuable, when in fact it is very useful in single-pill combinations.
If doctors are already using hydrochlorothiazide as an adjunct to other medications, then there’s no reason to change, as long as they’re happy with the results that they’re getting. Now, there is no doubt that chlorthalidone is a more powerful drug, and for some patients, it may be appropriate to turn to chlorthalidone to improve BP control. The problem with using chlorthalidone as an agent by itself is that it can cause hypokalemia, which is a troubling occurrence that usually requires physicians to modify the treatment regimen. Even so, chlorthalidone is a valuable drug that has proved effective for stroke and CV prevention in major clinical trials, and like hydrochlorothiazide can be used in combination with other drugs. That’s a perfectly appropriate thing to do. One of the newer angiotensin receptor blockers available in this country, azilsartan medoxomil (Edarbi, Takeda), comes in combination with chlorthalidone rather than hydrochlorothiazide, and has been shown to be a very powerful antihypertensive product.
At the same time, many physicians will continue to use hydrochlorothiazide in doses of 12.5 mg or 25 mg as a diuretic simply because it is part of combinations with so many drugs commonly used for treating hypertension.
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