Management of Hypertension
Hypertension is one of the few conditions in medicine that can be readily detected and effectively treated in the asymptomatic period before irreparable harm is done. It ranks as a leading risk factor for cardiovascular disease and as a major reason for office visits and the prescription of medication. Cardiovascular disease is the leading cause of death in the United States. Of these deaths, 83% are caused by myocardial infarction (MI) and 17% are from stroke. There has been a steady decline in cardiovascular death over the last three decades, at least some of which is attributable to the lowering of blood pressure in the general population. Awareness of hypertension has climbed to 81%, treatment to 71%, and control to 50%. The frequency and importance of hypertension demand that the primary physician be expert in its management and capable of designing a regimen that is safe, effective, and well-tolerated.
Over the past several decades, the Joint National Committee (JNC) has issued important guidelines representing the best expert opinion on management of hypertension. The latest iterations incorporate an increasing body of evidence from welldesigned trials, reducing the reliance on expert opinion. The two most recent reports (JNC 7 and JNC 8) form the basis for many of the recommendations in this chapter.
PRINCIPLES OF MANAGEMENT
The first tasks are to confirm the diagnosis and estimate the overall cardiovascular risk. This guides program design, which includes nonpharmacologic and pharmacologic interventions.
Confirming the Diagnosis
Because treatment of hypertension is likely to be lifelong, care must be taken to establish the diagnosis by correct blood pressure measurement and evaluation for possible contributing factors and secondary causes (see Chapters 14 and 19).
Staging
The assessment for treatment program design includes staging by degree of blood pressure elevation (Table 26-1 and Chapter 19). The Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has recommended eliminating the traditional designations of mild, moderate, and severe hypertension to avoid the misleading notion that mild hypertension is not a significant health risk. Instead, three stages are designated:
Prehypertension: Systolic blood pressure (SBP) 120 to 139 mm Hg and diastolic blood pressure (DBP) 80 to 89 mm Hg
Stage 1 hypertension: SBP 140 to 159 mm Hg and DBP 90 to 99 mm Hg
Stage 2 hypertension: SBP 160 mm Hg or greater and DBP 100 mm Hg or greater
Isolated Systolic Hypertension.
Isolated elevations in SBP (>140 mm Hg) confer significant cardiovascular risk, especially in older persons, regardless of the diastolic pressure. JNC underscores that “in persons older than 50 years, SBP of more than 140 mm Hg is a much more important cardiovascular disease risk factor than DBP.” In the elderly, a large pulse pressure is an independent predictor of cardiovascular risk.
Prehypertension.
There is no threshold blood pressure for cardiovascular risk. The risk of cardiovascular complications begins at pressures as low as 115/75 mm Hg and doubles with every 20-mm Hg increment of SBP and every 10-mm Hg increment for DBP. Persons with blood pressures in the so-called prehypertension range are at increased risk for developing sustained hypertension and cardiovascular complications. Cardiovascular risk is greatest in persons with concurrent diabetes, heart failure, renal insufficiency, or preexisting coronary artery disease. Although not all patients with prehypertension will go on to develop sustained elevation of blood pressure, a large percentage do. Those at highest risk for developing sustained hypertension can be identified by attention to age, sex, SBP and DBP, body mass index, parental hypertension, and smoking history.
Estimating Total Cardiovascular Risk
Because the ultimate goal of antihypertensive therapy is to reduce cardiovascular morbidity and mortality, the design of the treatment program must take into account the patient’s total cardiovascular risk, not simply the elevation in blood pressure. This assessment will determine the pace, intensity, and scope
of treatment. The task requires determining the degree of blood pressure elevation and identifying other cardiovascular risk factors (e.g., smoking, diabetes, hypercholesterolemia, age, gender, and family history), as well as any manifestations of target organ disease (e.g., left ventricular hypertrophy [LVH] with remodeling, retinopathy, nephrosclerosis, congestive heart failure [CHF], coronary artery disease, stroke, and peripheral vascular disease [see Chapter 19]). For any level of blood pressure elevation, the presence of such features dramatically raises the coronary disease risk from hypertension (e.g., from 9% over 10 years for a 40-year-old man with stage 1 hypertension to 70% for the same 40-year-old man if he also has elevated total cholesterol, a low high-density lipoprotein [HDL] cholesterol, diabetes, and LVH and smokes [see Appendix 26-1-26-26]). Because the risk of hypertension varies significantly depending on what other risk factors are present, the JNC has in the past emphasized an algorithm to guide treatment decisions based on assessment of total cardiovascular risk. In JNC 8, the goals of therapy have been relaxed a bit for high-risk groups due to lack of evidence of benefit from extra-tight control (see Table 26-1).
of treatment. The task requires determining the degree of blood pressure elevation and identifying other cardiovascular risk factors (e.g., smoking, diabetes, hypercholesterolemia, age, gender, and family history), as well as any manifestations of target organ disease (e.g., left ventricular hypertrophy [LVH] with remodeling, retinopathy, nephrosclerosis, congestive heart failure [CHF], coronary artery disease, stroke, and peripheral vascular disease [see Chapter 19]). For any level of blood pressure elevation, the presence of such features dramatically raises the coronary disease risk from hypertension (e.g., from 9% over 10 years for a 40-year-old man with stage 1 hypertension to 70% for the same 40-year-old man if he also has elevated total cholesterol, a low high-density lipoprotein [HDL] cholesterol, diabetes, and LVH and smokes [see Appendix 26-1-26-26]). Because the risk of hypertension varies significantly depending on what other risk factors are present, the JNC has in the past emphasized an algorithm to guide treatment decisions based on assessment of total cardiovascular risk. In JNC 8, the goals of therapy have been relaxed a bit for high-risk groups due to lack of evidence of benefit from extra-tight control (see Table 26-1).
TABLE 26-1 Management of Hypertension by Blood Pressure Stage and Risk Group | ||||||||||||||||||||
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Even modest elevation in blood pressure greatly increases risk, a very important fact from a population perspective. Most excess cardiovascular mortality from hypertension in the United States derives from patients with stage 1 disease (formerly referred to as “mild”), accounting for almost 80% of the hypertensive population and almost 60% of the excess cardiovascular mortality attributable to hypertension. Blood pressures in this range are not benign.
Further enhancements to risk stratification have been sought. The absence of the normal nocturnal reduction in pressure, as detected by ambulatory monitoring, independently contributes to prediction of cardiovascular risk. When there is a discrepancy between home/ambulatory determinations and office readings, risk more closely parallels that of the out-of-office readings.
Nonpharmacologic Measures (1,5,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22) (Table 26-2)
All patients are candidates for nonpharmacologic measures, which represent the foundation of treatment regimens for all stages. The principal nonpharmacologic measures include exercise (see Chapter 18), salt restriction, reduction of excess weight (see Chapter 233), and the use of a diet rich in potassium, magnesium, and calcium (the Dietary Approaches to Stop Hypertension [DASH] diet). These proven measures should be the foundation of every treatment program and also serve as an excellent means of primary prevention. Elimination of excess alcohol intake and chronic daily use of nonsteroidal antiinflammatory drugs (NSAIDs) are also important, as is avoidance of supplements and nonprescription drugs that can raise blood pressure (e.g., ephedra-containing herbal supplements and sympathomimetic decongestants). Behavioral therapies demonstrate an ability modestly to reduce pressure elevations but do not appear sufficient as the sole means of therapy in most patients. All nonpharmacologic measures should continue even if drug therapy needs to be instituted because they enhance its effectiveness and allow for the use of fewer medications at lower doses.
Exercise
Of the nonpharmacologic therapies, exercise is one of the most effective and should be a cornerstone of antihypertensive management. Its use may obviate the need for pharmacologic intervention in persons with mild hypertension, as evidenced by a study of aerobic and circuit weight training three times per week for 10 weeks, which revealed blood pressure reductions comparable to those achieved with β-blocker or calcium channel blocker (CCB) therapy obviating chronic drug treatment. Aerobic exercise provides multiple cardiovascular benefits, including weight reduction, cardiovascular conditioning, and improved lipid profile (see Chapter 18). In patients with mild uncomplicated hypertension, it should be a cornerstone. Candidates for a vigorous exercise program should undergo cardiac stress testing first (see Chapter 18).
Salt Restriction
Salt restriction is one of the mainstays of nonpharmacologic therapy for all hypertensive patients, regardless of underlying pathophysiology. Clear relationships between sodium excretion (a proxy for sodium intake) and risks of cardiovascular events have been established, with hazard ratios in the 1.50 to 1.60 range for cardiovascular death, nonfatal MI, stroke, and hospitalization for CHF. The overall degree of benefit for heterogeneous populations is rather modest when examined by meta-analysis of randomized trials (i.e., 3 to 5 mm Hg for SBP, 2 to 3 mm Hg for DBP), but it varies for individuals according
to their degree of salt sensitivity; African Americans and the elderly, who tend to have low-renin, volume-expanded hypertension, appear to respond particularly well to sodium restriction. Because we lack effective ways of identifying those most likely to respond to sodium restriction, all patients should be instructed in either a no-added-salt diet (4 g sodium/d) or a lowsodium diet (2 g/d), depending on their volume status. Current evidence finds a daily sodium limit of 1.5 g to be optimal (though hard to achieve). Not only may salt restriction alone provide adequate control in some mild cases, but it also can profoundly affect the efficacy of pharmacologic therapy. Patients receiving diuretics who had an unrestricted salt intake showed a blood pressure reduction of 4%, compared with a 15% reduction for those restricting their sodium intake.
to their degree of salt sensitivity; African Americans and the elderly, who tend to have low-renin, volume-expanded hypertension, appear to respond particularly well to sodium restriction. Because we lack effective ways of identifying those most likely to respond to sodium restriction, all patients should be instructed in either a no-added-salt diet (4 g sodium/d) or a lowsodium diet (2 g/d), depending on their volume status. Current evidence finds a daily sodium limit of 1.5 g to be optimal (though hard to achieve). Not only may salt restriction alone provide adequate control in some mild cases, but it also can profoundly affect the efficacy of pharmacologic therapy. Patients receiving diuretics who had an unrestricted salt intake showed a blood pressure reduction of 4%, compared with a 15% reduction for those restricting their sodium intake.
Weight Reduction and Other Dietary Measures
Weight reduction achieves significant decreases in blood pressure, even if ideal weight is not reached. This effect is independent of salt intake. All patients who are more than 15% above their ideal body weight should be urged to lose weight. In the Trial of Antihypertensive Interventions and Management study, patients receiving placebo who lost 4.5 kg or more of weight had the same reduction in pressure as those who maintained their usual diet and were treated with chlorthalidone or atenolol. The relation between obesity and blood pressure is particularly strong among young to middleaged adults. Weight loss is especially important in patients with central adiposity (hip-to-waist ratio >0.85 in women and >0.95 in men). Such patients have a higher incidence of hypertension, diabetes, and hyperlipidemia and a higher risk of cardiovascular disease. Weight loss in this group therefore reduces multiple risk factors simultaneously.
DASH Diet and Other Dietary Measures.
A dietary program rich in fruits, vegetables, and low-fat dairy products and limited in sodium (3 g/d), alcohol, and saturated fat makes an independent contribution to the treatment and prevention of hypertension even without achieving weight loss. Such a diet (sometimes referred to as the DASH diet for the study for which it was designed) is also rich in calcium, magnesium, and potassium. It demonstrates reductions of 11.4 mm Hg in SBP and 5.5 mm Hg in DBP. In mildly hypertensive participants, the DASH diet appears to be more effective than prescribing potassium, calcium, or magnesium supplements and demonstrates benefit across a broad spectrum of patient groups. Benefit is enhanced when the DASH diet is paired with additional salt restriction and other nonpharmacologic measures.
Observational studies find a modest reduction in blood pressure with the substitution of plant protein, specifically soy, for animal protein. Coffee consumption per se is not associated with an increased risk of hypertension, but the consumption of caffeinated cola drinks is, suggesting a possible benefit from limiting their intake.
Reduction in Excess Alcohol Consumption
Excessive alcohol intake is a frequent cause of “refractory” hypertension. Epidemiologic data also indicate a relationship between excess alcohol consumption and the risk of hypertension; daily intake in men of 2 oz of 100 proof whiskey, 10 oz of wine, or 24 oz of beer or more significantly increases the risk of becoming hypertensive; amounts are smaller for women.
Moderate alcohol consumption need not be curtailed. Alcohol intake of less than 1 oz/d equivalent may result in a modest decrease in blood pressure. Consumption of 2 oz or less per day has been linked to a decreased risk of MI but not of cardiovascular death.
Limiting Use of Nonsteroidal Anti-inflammatory Drugs
All NSAIDs inhibit cyclooxygenase-2 at the kidney level, with potential for antinatriuretic and vasoconstrictor effects. The chronic, daily use of prescription and nonprescription NSAIDs for arthritic pain is an underappreciated yet common phenomenon, especially among elderly hypertensive patients; it can impair blood pressure control and the action of antihypertensive agents, particularly diuretics and angiotensin blockers. Increases in SBP of 2 to 8 mm Hg have been observed, particularly among patients relying on renal prostaglandin synthesis for preservation of renal function, such as those with CHF. Compared to hypertensive patients with coronary disease not regularly using NSAIDs, those who do manifest a doubling of cardiovascular mortality. Checking for use, minimizing dose and frequency, and considering substitution of a non-NSAID analgesic (see Chapter 157) may help lower blood pressure, minimize need for pharmacologic treatment, and facilitate pharmacologic management.
Behavioral Therapies
Behavioral therapies such as relaxation techniques and biofeedback programs have been recommended for lowering blood pressure. Small-scale studies suggested a modest benefit, especially in patients with mild pressure elevations, but a rigorous metaanalysis of available studies found little specific benefit. Although behavioral techniques were superior to no therapy, they provided no more benefit than self-monitoring or sham techniques.
Comprehensive Lifestyle Modification
Comprehensive lifestyle modification can reduce blood pressure and cardiovascular risk. A randomized trial of multiple lifestyle interventions (PREMIER) that included the DASH diet, weight loss, exercise, and restriction of sodium and alcohol produced significant reductions in blood pressure, both in persons with mild hypertension and those with prehypertension. The magnitude of reductions approached that associated with single-drug pharmacologic therapy. The study underscored that, with comprehensive lifestyle modification, the development and progression of hypertension could be countered by nonpharmacologic means.
When to Initiate Drug Therapy
Pharmacologic measures require consideration when comprehensive lifestyle measures prove inadequate or when overall cardiovascular risk is high (Fig. 26-1 and Table 26-3). Persons with stage 2 hypertension, target organ damage, diabetes, or multiple cardiovascular risk factors (especially diabetes), and chronic kidney disease should be given consideration for pharmacologic therapy at the outset. For others, pharmacologic treatment can usually be deferred for weeks to months while the lifestyle modifications previously enumerated are instituted. If blood pressure does not normalize within 6 months, pharmacologic therapy should be initiated. Patients at the lowest level of risk (e.g., age <50 years, stage 1 disease, no diabetes, no chronic kidney disease, and no other cardiovascular risk factors or signs of target organ involvement) can probably delay pharmacologic therapy for 6 to 12 months while nonpharmacologic measures are tried (Fig. 26-1 and Table 26-1). On the other hand, pharmacologic therapy in elderly patients with isolated systolic hypertension should not be ignored, because patients older than 50 years of age have, as noted, a significantly increased risk of cardiovascular complications, which can be markedly reduced with drug
treatment. In JNC 8, the blood-pressure threshold for initiation of pharmacologic therapy in the general population 60 years and older has been raised to 150/90 mm Hg on the basis of seminal studies in the elderly.
treatment. In JNC 8, the blood-pressure threshold for initiation of pharmacologic therapy in the general population 60 years and older has been raised to 150/90 mm Hg on the basis of seminal studies in the elderly.
 Figure 26-1 2014 Hypertension guideline management algorithm. (SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEI, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker. aACEIs and ARBs should not be used in combination. bIf blood pressure fails to be maintained at goal, reenter the algorithm where appropriate based on the current individual therapeutic plan.) (From 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2013;doi:10.1001/jama.2013.284427.) |
Goals, Intensity, and Duration of Treatment
Consensus guidelines from the most recent JNC report provide helpful parameters, based on data that have emerged since the last report.
Treatment Goals.
The JNC 8 report recommends that blood pressure be lowered to less than 140/90 mm Hg for most patients under the age of 60 years, including those with diabetes and chronic kidney disease. For the latter two groups, this recommendation represents a relaxation in treatment goal from previous reports, based on evidence showing no benefit from tighter control. For persons 60 years and older, the treatment goal has been raised to <150/90, consistent with study findings.
When using home monitoring devices, the blood pressure goal for uncomplicated patients might be set at less than 135/85 mm Hg to take into account the lower readings typically recorded on home determinations (see Chapter 19).
Treatment goals might also include reduction in LVH, an important and treatable contributor to cardiovascular morbidity and mortality; reduction in left ventricular (LV) mass is accretive to outcomes associated with blood pressure reduction.
Intensity and Significance of the “J-Curve” Phenomenon.
Risk reduction appears to parallel the degree of reduction in blood pressure along a continuum of levels. However, the significance of the so-called J-curve phenomenon—an apparent increase in cardiovascular morbidity and mortality associated with marked decrease in blood pressure—has been a source of debate. Of particular concern is a marked reduction in DBP because most coronary perfusion takes place during diastole. In large-scale observational study of blood pressure treatment in hypertensive patients with coronary artery disease (an expectedly vulnerable population), the risk of all-cause death and MI began to increase as diastolic pressure decreased, especially at less than 70 mm Hg; however, there was no increase in the risk of stroke. This finding and data from meta-analysis study suggest that particular attention be paid to diastolic pressure during the treatment of hypertensive patients with known coronary disease and that care be taken not to lower diastolic pressure too aggressively.
Duration.
Because there is no cure for essential hypertension, drug treatment is often lifelong. Nonetheless, some patients with very mild hypertension may be able to stop medication, provided they continue nonpharmacologic measures and successfully control other risk factors. Even patients with substantial hypertension who require multidrug regimens may be candidates for a reduction in drug therapy. Patients with stage 1 disease whose blood pressure is well-controlled with pressures in the 120/80 mm Hg range for some months may be gradually
weaned off medication with the caveats that they need to continue nonpharmacologic measures and should be monitored periodically because pressures can slowly rise months after stopping therapy.
weaned off medication with the caveats that they need to continue nonpharmacologic measures and should be monitored periodically because pressures can slowly rise months after stopping therapy.
TABLE 26-2 Lifestyle Modifications for Managing Hypertension | |||||||||||||||||||||
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Selection of Initial Agent(s) (Table 26-3)
Pharmacologic therapy for essential hypertension remains largely empiric, guided in part by results of major prospective trials and a few generalizations about underlying mechanisms (e.g., sodium retention is common in the elderly and African Americans). Rapid advances in pharmacogenetics hold promise for a much more targeted and individualized approach to prescribing by improving the detection of underlying mechanisms and genetic polymorphisms that determine disease course and drug response (e.g., the α-adducin gene variant associated with salt-sensitive hypertension and response to diuretics).
In the meantime, consensus recommendations (based on largescale, long-term randomized trials demonstrating significant reductions in cardiovascular morbidity and mortality) remain the best guides to drug selection. JNC 8 recommends for the general nonblack population (including those with diabetes) first-line treatment with a thiazide diuretic, calcium-channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensinreceptor blocker (ARB), either alone or in combination. Major studies (e.g., ACCOMPLISH ALLHAT) suggest flexibility is warranted in selection of the initial agent, with any of these first-line agents a reasonable choice, refined by attention to patient characteristics. In black patients, including those with diabetes, JNC 8 notes evidence supporting initial therapy with a thiazide diuretic or a CCB. In those with chronic kidney disease, an ARB or ACEI is recommended for initial and add-on therapy. Ultimately, most patients require two or more drugs for adequate control, particularly those at heightened cardiovascular or renal risk.
The first-line drugs are comparable in efficacy. In a head-to-head, long-term, large-scale, prospective, randomized study (ALLHAT), the thiazide-like diuretic chlorthalidone proved just as effective as ACEI therapy (lisinopril) and CCB treatment (amlodipine) in reducing rates of fatal coronary heart disease, nonfatal MI, and all-cause mortality. In addition, diuretic therapy was superior to amlodipine in lowering the risk of heart failure and better than lisinopril at reducing the risks of heart failure, stroke, and combined forms of cardiovascular disease. Results were consistent across racial groups, with no significant differences in outcomes for blacks compared to nonblacks as regards benefits from thiazide-like diuretics compared to other first-line agents. ALLHAT also uncovered an unappreciated increase in risk of heart failure in older men taking the previously recommended first-line α-blocker agent doxazosin.
Beta-blockers had previously been considered first-line therapy for hypertension, but Cochrane review found no reduction in all-cause mortality. Nonetheless, reductions in rates of cardiovascular events have been noted, suggesting consideration of use in hypertensive patients at high cardiovascular risk or ongoing cardiovascular disease. Regardless of the medical regimen selected, all nonpharmacologic measures should be continued because they enhance the effectiveness of drug therapy and allow for the use of fewer medications at lower doses.
Selection of Subsequent Agents (Tables 26-3 and 26-4)
As long as there is a partial response to initial therapy, the dose of the first agent should be increased as necessary and as tolerated to achieve the desired blood pressure. If there is an initial response but target blood pressure has not been achieved, the dose may be further increased or a low dose of an agent from another first-line class can be added. However, if there is no response to the initial dose, then switching to a drug from another first-line class is recommended rather than adding a second agent. Although monotherapy suffices in some cases, most patients will require two or more medications to reach the goal. If thiazide is not the first drug, it should almost always be the second agent used because it enhances the effectiveness of all other antihypertensive agents, particularly in blacks. An ARB or ACEI should be added if not already started in persons with chronic kidney disease.
Cost Containment
Primary care physicians must consider affordability in the design of the antihypertensive regimen. Without attention to cost, the financial burden of a lifelong pharmacologic program can easily become so great that patients fill only part of a prescription or cut frequency or dose, compromising compliance and threatening blood pressure control. Fortunately, most thiazides and ACEIs are now available generically at much reduced cost, as are many CCBs and an increasing number of ARBs.
The reaffirmation of the effectiveness of generically available first-line agents in randomized, prospective, head-to-head study should help to control the cost of treatment. Their very low cost, ease of use, and excellent efficacy across a wide range of patients make them an essential consideration for every hypertensive treatment program. Additional approaches to minimizing cost include substituting a sustained-release preparation if it is less expensive than a multidose regimen; staying with a less-expensive, older antihypertensive agent if it is reasonably effective and well-tolerated; and using the lowest dose possible.
TABLE 26-3 Evidence-Based Dosing for Antihypertensive Drugs | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Maximizing Compliance
Maintaining as simple a program as possible facilitates compliance, with the best rates seen for programs that require a limited number of pills taken once or twice daily. Cost is also an essential consideration but becoming less of a factor with the conversion of most antihypertensive drugs to generic formulations. A host of interventions have been recommended. Randomized trials find that home monitoring of blood pressure and behavioral coaching by nurses can be helpful, particularly for persons with inadequately controlled hypertension. Combination approaches appear best, but there is some decay over time in the effect of behavioral coaching.
TABLE 26-4 Strategies to Dose Antihypertensive Drugs | |||||||||||||||||||||
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Pharmacologic Therapy: First-Line Agents (1,4,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 and 55) (Table 26-3)
Thiazide Diuretics
These agents are experiencing a renaissance of use as the first choice for pharmacologic therapy, based on findings from the landmark ALLHAT study (see prior discussion), which documented long-term outcomes equal to or better than those achieved with ACEIs, CCBs, or α-blockers (there were no direct comparisons with β-blockers). The thiazide-like agent chlorthalidone produced comparable reductions in blood pressure and LVH and similar or superior reductions in risks of
cardiovascular morbidity and mortality. Such proven efficacy, combined with safety and extremely low cost, makes thiazides a compelling first choice for the pharmacologic management of hypertension (Table 26-3). In addition to chlorthalidone, agents included in this class are hydrochlorothiazide (HCTZ) (the most widely prescribed thiazides in the United States), indapamide (commonly used outside the United States), and metolazone.
cardiovascular morbidity and mortality. Such proven efficacy, combined with safety and extremely low cost, makes thiazides a compelling first choice for the pharmacologic management of hypertension (Table 26-3). In addition to chlorthalidone, agents included in this class are hydrochlorothiazide (HCTZ) (the most widely prescribed thiazides in the United States), indapamide (commonly used outside the United States), and metolazone.
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