Treatment

Blood Pressure Control Rates

Hypertension is the most common primary diagnosis in America (35 million office visits as the primary diagnosis).⁵ Current control rates (SBP <140 mmHg and DBP <90 mmHg), though improved, are still far below the Healthy People goal of 50 percent, which was originally set as the year 2000 goal and has since been extended to 2010 (see table 1). In the majority of patients, reducing SBP has been considerably more difficult than lowering DBP. Although effective BP control can be achieved in most patients who are hypertensive, the majority will require two or more antihypertensive drugs.^28,29,86 Failure to prescribe lifestyle modifications, adequate antihypertensive drug doses, or appropriate drug combinations may result in inadequate BP control.

Goals of Therapy

The ultimate public health goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. Since most persons with hypertension, especially those >50 years of age, will reach the DBP goal once the SBP goal is achieved, the primary focus should be on attaining the SBP goal. Treating SBP and DBP to targets that are <140/90 mmHg is associated with a decrease in CVD complications.⁸⁷ In patients with hypertension and diabetes or renal disease, the BP goal is <130/80 mmHg.^88,89

Benefits of Lowering Blood Pressure

In clinical trials, antihypertensive therapy has been associated with reductions in (1) stroke incidence, averaging 35–40 percent; (2) myocardial infarction (MI), averaging 20–25 percent; and (3) HF, averaging >50 percent.⁹⁰ It is estimated that in patients with stage 1 hypertension (SBP 140–159 mmHg and/or DBP 90–99 mmHg) and additional cardiovascular risk factors, achieving a sustained 12 mmHg reduction in SBP over 10 years will prevent 1 death for every 11 patients treated. In the added presence of CVD or target organ damage, only nine patients would require such BP reduction to prevent one death.⁹¹

Lifestyle Modifications

Adoption of healthy lifestyles by all persons is critical for the prevention of high BP and is an indispensable part of the management of those with hypertension.¹⁰ Weight loss of as little as 10 lbs (4.5 kg) reduces BP and/or prevents hypertension in a large proportion of overweight persons, although the ideal is to maintain normal body weight.^92,93 BP is also benefited by adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan⁹⁴ which is a diet rich in fruits, vegetables, and lowfat dairy products with a reduced content of dietary cholesterol as well as saturated and total fat (modification of whole diet). It is rich in potassium and calcium content.⁹⁵ Dietary sodium should be reduced to no more than 100 mmol per day (2.4 g of sodium).^94–96 Everyone who is able should engage in regular aerobic physical activity such as brisk walking at least 30 minutes per day most days of the week.^97,98 Alcohol intake should be limited to no more than 1 oz (30 mL) of ethanol, the equivalent of two drinks per day in most men and no more than 0.5 oz of ethanol (one drink) per day in women and lighter weight persons. A drink is 12 oz of beer, 5 oz of wine, and 1.5 oz of 80-proof liquor (see table 9).⁹⁹ Lifestyle modifications reduce BP, prevent or delay the incidence of hypertension, enhance antihypertensive drug efficacy, and decrease cardiovascular risk. For example, in some individuals, a 1,600 mg sodium DASH eating plan has BP effects similar to single drug therapy.⁹⁴ Combinations of two (or more) lifestyle modifications can achieve even better results.¹⁰⁰ For overall cardiovascular risk reduction, patients should be strongly counseled to quit smoking.

Pharmacologic Treatment

A large number of drugs are currently available for reducing BP. Tables 10 and 11 provide a list of the commonly used antihypertensive agents, and their usual dose range and frequency of administration.

More than two-thirds of hypertensive individuals cannot be controlled on one drug and will require two or more antihypertensive agents selected from different drug classes.^{28,87,101–103} 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.²⁸ 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.^104–108 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.^{90,101,102,107,109–112} Several randomized controlled trials have demonstrated reduction in CVD with BBs, but the benefits are less consistent than with diuretics.^107,108 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.¹¹³ 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).¹¹⁰ 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.¹¹⁴

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.^{101,102,109,112,115–118} 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.¹⁰² 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,¹⁰⁹ 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.¹¹² CVD outcome data comparing ARB with other agents are limited.

Clinical trial data indicate that diuretics are generally well tolerated.^103,109 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 12.5–25 mg 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.^119–122

Uric acid will increase in many patients receiving a diuretic, but the occurrence of gout is uncommon with dosages ≤50 mg/day of hydrochlorothiazide or ≤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.¹²³ The VA Cooperative study did not document a significant difference in the occurrence of sexual dysfunction using diuretics when compared with other antihypertensive medications¹⁰³ (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.¹⁰⁹ 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.^124,125 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.¹⁰⁹ Thiazide-induced 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.¹²¹ 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.¹²⁶ However, other studies have not demonstrated increased ventricular ectopy as a result of diuretic therapy.¹²⁷ 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.¹²⁸

Achieving Blood Pressure Control in Individual Patients

The algorithm for the treatment of hypertensive patients is shown in figure 16. 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. Selection of one of these other agents as initial therapy is recommended when a diuretic cannot be used or when a compelling indication is present that requires the use of a specific drug, as listed in table 12. If the initial drug selected is not tolerated or is contraindicated, then a drug from one of the other classes proven to reduce cardiovascular events should be substituted.

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.¹²⁹ (See figure 16.)

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.^129,130

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.

Followup and Monitoring

Once antihypertensive drug therapy is initiated, most patients should return for followup and adjustment of medications at monthly intervals or until the BP goal is reached. More frequent visits will be necessary for patients with stage 2 hypertension or with complicating comorbid conditions. Serum potassium and creatinine should be monitored at least one to two times per year. After BP is at goal and stable, followup visits can usually be at 3- to 6-month intervals. Comorbidities such as HF, associated diseases such as diabetes, and the need for laboratory tests influence the frequency of visits. Other cardiovascular risk factors should be monitored and treated to their respective goals, and tobacco avoidance must be promoted vigorously. Low-dose aspirin therapy should be considered only when BP is controlled because of the increased risk of hemorrhagic stroke when the hypertension is not controlled.¹³¹