Hydrochlorothiazide for Hypertension: Is It the Diuretic of Choice?

Hypertension (HTN) is one of the most common disease states in the developed world, with an estimated prevalence of 30% in the United States.¹ The primary goal of hypertension treatment is a reduction in cardiovascular (CV) events such as myocardial infarction and stroke, as well as slowing the progression to or the worsening of chronic kidney disease. HTN has a role in many other disease states as well. Blood pressure (BP) is utilized as a surrogate marker for CV events, as well as to monitor the safety and efficacy of antihypertensive treatment.²

Numerous treatment guidelines from national and international organizations have been published, and most of them recommend thiazide diuretics (or thiazide-type diuretics, hereafter considered interchangeable with thiazide diuretics) as a first-line treatment option for patients with uncontrolled HTN. Nevertheless, many organizations’ guidelines do not specify a preferred thiazide diuretic.³ While numerous thiazide diuretics are available, hydrochlorothiazide (HCTZ) is by far the most commonly used diuretic in the United States, with an estimated 50 million prescriptions written annually.⁴ Notable alternatives to HCTZ include indapamide and chlorthalidone (CTD). Given the widespread use of HCTZ, does the currently available data confirm its role as the apparent preferred thiazide diuretic?

Case Report

JG is a 55-year-old black man with a history of tobacco use (his quit date was October 1, 2012) and hyperlipidemia. One month ago, his BP was noted to be elevated during a routine follow-up visit, and upon repeat check today it remains elevated at 158/95 mm Hg, thus establishing a new diagnosis of HTN. 

National guidelines² recommended that he be started on a thiazide diuretic or a calcium-channel blocker. If a thiazide diuretic were desired, which agent would be preferred?

Diuretic Comparison: Kinetics

HCTZ is by far the mostly commonly utilized thiazide diuretic, while CTD and indapamide are used less frequently. Clearly, the goal of antihypertensive therapy is 24-hour BP control, but interestingly, not all diuretics have a half-life that is at least 24 hours to support once-daily dosing (Table).⁵ 

CTD is sometimes cited as having a higher risk of inducing hypokalemia compared with other diuretics, namely HCTZ, but this could be related in part to both the half-life and the potency: The longer duration of action would allow for more time to elicit hypokalemic effects, and, if compared on the same milligram-per-milligram dose, the higher potency of CTD would be expected to lead to a higher incidence of hypokalemia. When dosed equivalently, it seems reasonable that hypokalemic effects would become more similar between CTD and HCTZ, but CTD still may have a slightly higher risk given its longer duration of action. However, while this longer duration of action may contribute to a slightly higher incidence of adverse effects, it could be tied to a difference in CV event rates compared with HCTZ.⁵

Diuretic Comparison: BP and CV Events

Patients are counseled to take their diuretic the first thing in the morning in an effort to limit nocturia associated with taking the diuretic close to bedtime (this effect may diminish over time). However, morning dosing may lead to differences in assessment of efficacy of BP lowering based on the agent used.

Because HCTZ only has a half-life of roughly 12 hours, dosing at 8 am would be expected to lead to BP-lowering effects until approximately 8 pm. Because most home BP monitoring and physician visits occur during these hours, the patient’s BP may appear to respond favorably to HCTZ and lead the clinician and patient to believe that HCTZ therapy is successfully controlling BP. However, nighttime BP, suggested to be the most prognostic type of BP for future CV events,⁶ will not be similarly controlled as the daytime BP, given the short half-life of HCTZ.

It is important to remember that the main goal of antihypertensive therapy is a reduction in CV events, which hopefully would be accompanied by a reduction in BP, but similar BP values does not always equate to equivalent outcomes. The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial⁷ clearly illustrates this point: Patients with HTN were randomly assigned to either an angiotensin-converting enzyme inhibitor (perindopril) plus amlodipine (P + A) or perindopril plus HCTZ (P + H) and followed for an average 36 months to evaluate the efficacy in reducing CV events. At the conclusion of the study, BP between the groups was nearly identical (131.6/73.3 mm Hg vs 132.5/74.4 mm Hg), but a significant reduction in CV events was seen in the patients receiving P + A compared with P + H (event rate, 9.6% vs 11.8%; relative risk reduction, 19.6%; absolute risk reduction, 2.2%; P < .001; number needed to treat, ~43). While BP is a significant and important surrogate marker for CV events, this study clearly demonstrates that not all BPs are created equal with regards to a reduction in CV events.

Given that the focus of antihypertensive therapy should be on a reduction in outcomes (and not solely on a reduction in BP), the agents that are utilized should have a clearly documented benefit in reducing CV events. CTD was the thiazide diuretic utilized in ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) (n = 33,357), whereas indapamide was utilized in HYVET (Hypertension in the Very Elderly Trial) (n = 3,845). On the contrary, there is no evidence that HCTZ as monotherapy clearly and consistently reduces CV outcomes despite its perceived benefits with regards to BP lowering; indeed, the ACCOMPLISH trial showed the inferiority of an HCTZ-perindopril regimen compared with an amlodipine-perindopril regimen.⁸

Clinical Application

Based on the available pharmacokinetic data (showing only a 12-hour half-life), combined with a lack of positive outcome data and a study with negative results (ACCOMPLISH), it does not appear that HCTZ should be the thiazide diuretic of choice. CTD and indapamide both have outcome data showing a clear benefit in reducing CV events, and both agents have pharmacokinetic profiles that better meet the requirements of 24-hour BP control. While HCTZ is commonly available on $4 medication lists at pharmacies, CTD and indapamide also are inexpensive and should have similar copayments for patients with insurance, and so cost in most cases should not be a rate-limiting factor. Again, the importance of a documented reduction in CV events should be placed above data showing only a reduction in BP, so agents with documented CV reduction should be preferred. Therefore, HCTZ monotherapy, especially when dosed once daily, should not have a role in the treatment of HTN if CTD or indapamide are viable options.

Outcome of the Case

JG has elevated BP on 2 consecutive and separate clinic visits, meeting the diagnostic criteria for HTN. Since a thiazide diuretic is preferred, an agent with documented CV event reduction should be selected. 

Because HYVET was in patients aged 80 years and older,⁹ and the mean age of participants in ALLHAT was 67 years,⁸ JG would be started on CTD, 12.5 mg daily in the morning. His kidney function (via serum creatinine level) and results of a basic metabolic panel should be rechecked in 1 week to ensure no electrolyte abnormalities have occurred. His BP will be rechecked in 4 weeks, and he will be encouraged to check his BP frequently at home for additional safety and efficacy monitoring.

Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.

Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.

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