MODULE 2: Rethinking the Role of Thiazide-Type Diuretics in the Management of Hypertension: Which Diuretic Is Best?
Dr Cushman is a paid consultant to Daiichi-Sankyo, Inc; Merck & Co, Inc; Omron Healthcare, Inc; and Takeda Pharmaceuticals International, Inc. He has performed contracted research for Merck & Co, Inc.
Despite the availability of 7 major classes of effective and safe antihypertensive medications and numerous combination drugs designed to reduce pill burden and improve adherence, just 50.1% of the estimated 76.4 million US adults with hypertension (33.5% of the population) have their condition under control.1
One of the greatest challenges for clinicians who manage patients with hypertension is choosing the most appropriate drug, whether as initial treatment or add-on therapy. Clinicians may be guided in this decision, however, by guidelines and algorithms that are provided for hypertension management. These algorithms are reviewed in the first article in this supplement by Dr William B. White.
National guidelines recommend thiazide-type diuretics as initial therapy for most patients with hypertension, regardless of the severity of the condition, either alone or in combination with 1 of the other classes of hypertension medications that have also been shown to reduce 1 or more hypertensive complications in randomized controlled outcome trials.2,3 These recommendations are based primarily on more than 50 years of data on the safety and efficacy of thiazide-type diuretics.
The first evidence of the benefits of thiazide-type diuretics came from publications of the VA (Veterans Administration) Cooperative Study in 1967 and 1970. It was the first trial to demonstrate reduced stroke, heart failure (HF), and progressive kidney damage in patients receiving antihypertensive treatment, including the then-newly released hydrochlorothiazide (HCTZ), a thiazide diuretic.4
Since then, hundreds of clinical trials have demonstrated the efficacy of thiazide-type diuretics. During that time, however, numerous other classes of antihypertensive medications were introduced, leading to the question of the appropriate place of thiazides within the antihypertensive arsenal. The seminal trial to answer this question was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This randomized, double-blind, multicenter, clinical trial was designed to determine whether the occurrence of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) was lower for high-risk hypertensive patients 55 years of age and older who were treated with the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, or the alpha-blocker doxazosin compared with the thiazide-type diuretic chlorthalidone (CTD).5 Investigators could add atenolol, clonidine, reserpine, and/or hydralazine as necessary to achieve blood pressure (BP) goal. The trial randomized 42,418 patients, 90% of whom had been previously treated.
At a mean follow-up of 4.9 years, there was no significant difference in the primary outcome or mortality between the 4 drugs.5 There was a 38% higher rate of HF with amlodipine, and a 10%, 15%, and 19% higher rate of cardiovascular disease (CVD), stroke, and HF, respectively, with lisinopril compared with CTD. For stroke, there was a statistically significant race-by-treatment interaction (40% higher stroke rate with lisinopril vs CTD in black participants). Participants in the doxazosin treatment group (n = 9061) were followed for a mean of 3.2 years. This arm was terminated early because of a 25% higher incidence of CVD events, including a nearly 2-fold higher risk of HF, accompanied by a low probability of reaching a statistically significant difference in the primary endpoint.5
Additional rationale for the use of diuretics in elderly populations came from the Systolic Hypertension in the Elderly Program (SHEP), a multicenter, randomized, double- blind, placebo-controlled trial of patients aged 60 years and older.6 Participants were randomized to either CTD 12.5 to 25 mg once daily±atenolol 25 to 50 mg once daily, or reserpine 0.05 mg once daily, or placebo. Treatment reduced the incidence of all fatal and nonfatal strokes by 36%, MI by 27%, all CHD by 27%, and all CVD by 32%.6
Underuse of diuretics
Despite trials such as SHEP and ALLHAT, and despite the long record of safety and efficacy in numerous patient populations, thiazide-type diuretics remain significantly under-used in clinical practice.7-10
Even intensive academic detailing designed to increase the use of thiazide-type diuretics found that the prescribing rates of 37.1% immediately before the intervention only increased to 39.6% overall after the intervention (46.5% in areas that received the most intensive intervention), reflecting what appears to be clinical resistance to this class of drugs (FIGURE 1).11 Even 4 years after the ALLHAT results were published, national use of thiazide-type drugs had not increased significantly.12