The Choice of Thiazide Diuretics

T hiazide diuretics were introduced in the United States for the treatment of hypertension in 1957.The first of these, chlorothiazide, was soon accompanied by a large number of other sulfonamide derivatives, including chlorthalidone.Hydrochlorothiazide (HCTZ) rapidly became the most commonly prescribed antihypertensive drug in the United States, whereas bendroflumethiazide was most popular in the United Kingdom.The initial popularity of HCTZ in the United States was abetted by its use in the first controlled trial of the treatment of nonmalignant hypertension, the Veterans' Affairs Cooperative Study. 1 The starting dose of HCTZ was 50 mg/d, and it was used along with reserpine and hydralazine.A number of other trials published in the 1970s all used higher doses of diuretic, for example, Ն50 mg of HCTZ per day. 2 For reasons unknown to me, chlorthalidone was chosen to be the diuretic in the first large controlled trial of the treatment of hypertension, the Hypertension Detection and Follow-Up Program. 3 In the Hypertension Detection and Follow-Up Program, all 10 940 patients were started on chlorthalidone from 25 to 100 mg/d.Other drugs were added to achieve control of the blood pressure.In addition, half were assigned to "referred" care and the other half to more closely monitored and intensively treated "stepped" care.The stepped care-treated half achieved a 4.4% further reduction in diastolic blood pressure and a 17.0% reduction in mortality.In other large, placebo controlled trials published in the early 1980s, other diuretics were used: chlorothiazide in the Australian trial, 4 HCTZ in the Oslo study, 5 and bendrofluazide in the United Kingdom Medical Research Council Trial.6 In all of these trials, the diuretic was combined with other drugs to achieve the goal of therapy.When the Multiple Risk Factor Intervention Trial was begun, either chlorthalidone or HCTZ, both at doses of 50 or 100 mg daily, could be used.In 6 clinics, chlorthalidone was chosen; in 9, HCTZ was used.After some 7 years, the Multiple Risk Factor Intervention Trial Policy Advisory Board recommended that all of the subjects be given chlorthalidone at a maximal dose of 50 mg/d, because the trend of mortality was unfavorable in the 9 clinics using HCTZ compared with the favorable trend in the 6 clinics using chlorthalidone.7 Nonetheless, HCTZ has been much more widely prescribed in the United States than chlorthalidone and, except for combination with a ␤-blocker (atenolol) and a central ␣ agonist (clonidine), all of the many other available combinations with a diuretic contain HCTZ at doses ranging from 6.25 mg to 25.00 mg per day. 2 Moreover, the multiple Joint National Committee reports only recommend a thiazide diuretic without choosing the specific agent.8