A large number of drugs are currently available for reducing BP. Greater than 2/3 of all patients treated for hypertension will need more than one agent. For example, in ALLHAT, 60 percent of those whose BP was controlled to <140/90 mmHg received two or more agents, and only 30 percent overall were controlled on one drug. In hypertensive patients with lower BP goals or with substantially elevated BP, three or more antihypertensive drugs may be required. Since the first VA Cooperative Trial, published in 1967, thiazide-type diuretics have been the basis of antihypertensive therapy in the majority of placebo-controlled outcome trials, in which CVD events, including strokes, CHD, and HF have been reduced by BP lowering. However, there are also excellent clinical trial data proving that lowering BP with other classes of drugs, including ACEIs, ARBs, beta blockers (BBs), and calcium channel blockers (CCBs) also reduces the complications of hypertension. Several randomized controlled trials have demonstrated reductions in CVD with BBs, but the benefits are less consistent than with diuretics. The European Trial on Systolic Hypertension in the Elderly (Syst-EUR) showed significant reductions in stroke and all CVD with the dihydropyridine CCB, nitrendipine, as compared with placebo. The Heart Outcomes Prevention Evaluation (HOPE) Study, which was not restricted to hypertensive individuals but which included a sizable hypertensive subgroup, showed reductions in a variety of CVD events with the ACEI, ramipril, compared with placebo in individuals with prior CVD or diabetes mellitus combined with other risk factor(s). The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study in which the ACEI, perindopril, was added to existent therapy in patients with stable coronary disease and without HF also demonstrated reduction in CVD events with ACEIs.
Since 1998, several large trials comparing “newer” classes of agents, including CCBs, ACEIs, an alpha-1 receptor blocker, and an ARB, with the “older” diuretics and/or BBs have been completed. Most of these studies showed the newer classes were neither superior nor inferior to the older ones. One exception was the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study, in which CVD events were 13 percent lower (because of differences in stroke but not CHD rates) with the ARB, losartan, than with the BB, atenolol.
There has not been a large outcome trial completed yet comparing an ARB with a diuretic. All of these trials together suggest broadly similar cardiovascular protection from BP-lowering with ACEIs, CCBs, and ARBs, as with thiazide-type diuretics and BBs, although some specific outcomes may differ between the classes. There do not appear to be systematic outcome differences between dihydropyridine and nondihydropyridine CCBs in hypertension morbidity trials. On the basis of other data, short-acting CCBs are not recommended in the management of hypertension.
Rationale for Recommendation of Thiazide-Type Diuretics as Preferred Initial Agent
In trials comparing diuretics with other classes of antihypertensive agents, diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension. In the ALLHAT study, which involved more than 40,000 hypertensive individuals, there were no differences in the primary CHD outcome or mortality between the thiazide-type diuretic, chlorthalidone; the ACEI, lisinopril; or the CCB, amlodipine. Stroke incidence was greater with lisinopril than chlorthalidone therapy, but these differences were present primarily in African Americans who also had less BP lowering with lisinopril than diuretics. The incidence of HF was greater in CCB-treated and ACEI-treated individuals as compared with those receiving the diuretic in both African Americans and Whites. In the Second Australian National Blood Pressure (ANBP2) Study, which compared the effects of an ACEI-based regimen against diuretics-based therapy in 6,000 White hypertensive individuals, cardiovascular outcomes were less in the ACEI group, with the favorable effect apparent only in men. CVD outcome data comparing ARB with other agents are limited.
Clinical trial data indicate that diuretics are generally well tolerated. The doses of thiazide-type diuretics used in successful morbidity trials of “low-dose” diuretics were generally the equivalent of 25–50 mg of hydrochlorothiazide or 12.5–25mg of chlorthalidone, although therapy may be initiated at lower doses and titrated to these doses if tolerated. Higher doses have been shown to add little additional antihypertensive efficacy, and are associated with more hypokalemia and other adverse effects.
Uric acid will increase in many patients receiving a diuretic, but the occurrence of gout is uncommon with dosages of 50 mg/day of hydrochlorothiazide or of 25 mg of chlorthalidone. Some reports have described an increased degree of sexual dysfunction when thiazide diuretics (particularly at high doses) are used. In the Treatment of Mild Hypertension Study (TOMHS), participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months of the study; however, the incidence rate at 48 months was similar to placebo. The VA Cooperative study did not document a significant difference in the occurrence of sexual dysfunction using diuretics when compared with other antihypertensive medications (see section on erectile dysfunction). Adverse metabolic effects may occur with diuretics. In ALLHAT, diabetes incidence after 4 years of therapy was 11.8 percent with chlorthalidone therapy, 9.6 percent with amlodipine, and 8.1 percent with lisinopril. However, those differences did not translate to fewer cardiovascular events for the ACEI or CCB groups.
Those who were already diabetic had fewer cardiovascular events in the diuretic group than with ACEI treatment. Trials of longer than 1 year’s duration using modest doses of diuretics generally have not shown an increase in serum cholesterol in diuretic-treated patients. In ALLHAT, serum cholesterol did not increase from baseline in any group, but it was 1.6 mg/dL lower in the CCB group and 2.2 mg/dL lower in the ACEI group than in diuretic-treated patients. Thiazideinduced hypokalemia could contribute to increased ventricular ectopy and possible sudden death, particularly with high doses of thiazides in the absence of a potassium-sparing agent. In the Systolic Hypertension in the Elderly Program (SHEP) Trial, the positive benefits of diuretic therapy were not apparent when serum potassium levels were below 3.5mmol/L. However, other studies have not demonstrated increased ventricular ectopy as a result of diuretic therapy. Despite potential adverse metabolic effects of diuretics, with laboratory monitoring, thiazide-type diuretics are effective and relatively safe for the management of hypertension.
Thiazide diuretics are less expensive than other antihypertensive drugs, although as members of other classes of drugs have become available in generic form, their cost has been reduced. Despite the various benefits of diuretics, they remain underutilized.
Achieving Blood Pressure Control in Individual Patients
Therapy begins with lifestyle modification, and if BP goal is not achieved, thiazide-type diuretics should be used as initial therapy for most patients, either alone or in combination with one of the other classes (ACEIs, ARBs, BBs, CCBs) that have also been shown to reduce one or more hypertensive complications in randomized controlled outcome trials.
Since most hypertensive patients will require two or more antihypertensive medications to achieve their BP goals, addition of a second drug from a different class should be initiated when use of a single agent in adequate doses fails to achieve the goal. When BP is >20 mmHg above systolic goal or 10 mmHg above diastolic goal, consideration should be given to initiate therapy with two drugs, either as separate prescriptions or in fixed-dose combinations. The initiation of therapy with more than one drug increases the likelihood of achieving BP goal in a more timely fashion. The use of multidrug combinations often produce greater BP reduction at lower doses of the component agents, resulting in fewer side effects.
The use of fixed-dose combinations may be more convenient and simplify the treatment regimen, and may cost less than the individual components prescribed separately. Use of generic drugs should be considered to reduce prescription costs, and the cost of separate prescription of multiple drugs available generically may be less than nongeneric, fixed-dose combinations. The starting dose of most fixed-dose combinations is usually below the doses used in clinical outcome trials, and the doses of these agents should be titrated upward to achieve the BP goal before adding other drugs. However, caution is advised in initiating therapy with multiple agents, particularly in some older persons and in those at risk for orthostatic hypotension, such as diabetics with autonomic dysfunction.