Ovid: Primary Care Medicine

Chapter 26

Management of Hypertension

Katharine K. Treadway

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 prescription of medication. Cardiovascular disease is the leading cause of death in the United States. Of these deaths, 83% are caused by myocardial infarction 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. 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.

PRINCIPLES OF MANAGEMENT

The first tasks are to confirm the diagnosis and estimate overall cardiovascular risk. This guides program design, which includes nonpharmacologic and pharmacologic interventions.

Confirming The Diagnosis And Classifying By Severity (1)

Because treatment of hypertension is likely to be lifelong, it is essential that the diagnosis be well established before committing the patient to therapy. Initiation of antihypertensive treatment should be preceded by a careful evaluation that not only confirms the diagnosis, but also rules out secondary causes, identifies any additional cardiovascular risk factors, and assesses presence and degree of target-organ damage (see Chapters 14 and 19).

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, a national consensus group, has issued several reports, which include recommendations for the classification of hypertension. In its most recent report, JNC VII, it has continued to recommend eliminating the traditional designations of “mild,” “moderate,” and “severe” hypertension to avoid the misleading notion than mild hypertension is not a significant health risk. Instead, they designate three stages:

Prehypertension: diastolic blood pressure (DBP) 80 to 89 mm Hg; systolic blood pressure (SBP) 120 to 139 mm Hg
Stage 1—DBP 90 to 99 mm Hg; SBP 140 to 159 mm Hg
Stage 2—DBP 100 mm Hg or greater; SBP 160 mm Hg or greater

Prehypertension is designated to highlight the increased risk of developing sustained hypertension in this group (see Chapter 19, Table 19.1). It should also be noted that isolated systolic hypertension is an equally significant predictor of cardiovascular risk, regardless of the diastolic pressure. In fact, a large pulse pressure in elderly patients is an independent predictor of cardiovascular risk.

Table 26.1. Management of Hypertension by Blood Pressure Stage and Risk Group

Blood Pressure Stage	Risk Group A	Risk Group B	Risk Group C
High normal (130–139/85–89 mm Hg)	Lifestyle modification	Lifestyle modification	Drug prescription if diabetes mellitus, congestive heart failure, or renal insufficiency Lifestyle modification
Stage 1 (140–159/90–99 mm Hg)	Lifestyle modification (up to 12 mo)	Lifestyle modification (up to 6 mo) Initial drug prescription for patients with multiple risks	Drug prescription Lifestyle modification
Stages 2 and 3 (>160/100 mm Hg)	Drug prescription	Drug prescription	Drug prescription
	Lifestyle modification	Lifestyle modification	Lifestyle modification
Goals of therapy:
In most patients: <140/90 mm Hg
In diabetic patients: <130/85 mm Hg
In patients with renal failure and proteinuria (>1 g in 24 hr): <125/75 mm Hg
In elderly patients with severe systolic hypertension: systolic blood pressure <160 mm Hg is reasonable if attempts to reach 140 mm Hg result in intolerable side effects
Risk Group A, no major risk factors, no target-organ damage/clinical cardiovascular disease; Risk Group B, at least one major risk factor, not diabetes mellitus, no target-organ damage/clinical cardiovascular disease; Risk Group C, target-organ damage/clinical cardiovascular disease and/or diabetes mellitus with or without other risk factors.
Major risk factors: smoking, dyslipidemia, diabetes mellitus, age >60 yr, male gender, postmenopausal women, family history.
Adapted from Chobanian AV, Bakris GL, Cushman WC, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC VII report. JAMA 2003:289;2560, with permission.

Estimating Total Cardiovascular Risk (1,2,3,4,5)

Because the goal of antihypertensive therapy is to reduce cardiovascular morbidity and mortality, the treatment program must address the patient's total cardiovascular risk, not simply the elevation in blood pressure. This will determine the pace, intensity, and scope of treatment. Consequently, estimation of total cardiovascular risk becomes the first priority in program design. 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 with remodeling [LVH], retinopathy,

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nephrosclerosis, congestive heart failure [CHF], coronary artery disease, stroke, or peripheral vascular disease; see Chapter 19). For any level of blood pressure elevation, the presence of such features dramatically accelerates the risk from hypertension. For example, the risk of a 40-year-old man developing coronary disease in the next 10 years with stage 1 to 2 hypertension (formerly known as mild to moderate disease) is about 9%. If that same 40-year-old man also has elevated cholesterol, a low high-density lipoprotein (HDL), diabetes, LVH on electrocardiogram, and smokes, risk increases to about 60% (see Appendix). Because the risk of hypertension varies significantly depending on what other risk factors are present, JNC has proposed an algorithm to guide treatment decisions. It should be noted that the presence of diabetes confers such significant risk that it is treated as equivalent to the presence of overt cardiovascular disease (Table 26.1).

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 called 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.

Nonpharmacologic Management (1,6,7,8,9,10,11,12,13,14,15)

The principal nonpharmacologic measures for treatment of hypertension (Table 26.2) include exercise, salt restriction, reduction of excess weight (see Chapter 233), and use of a diet rich in potassium, magnesium, and calcium (the Dietary Approaches to Stop Hypertension [DASH] diet). These proven

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measures should be the foundation of every treatment program and also serve as an excellent means of primary prevention. Elimination of excess alcohol intake is also important. Behavioral therapies demonstrate an ability to modestly 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 use of fewer medications at lower doses.

Table 26.2. Lifestyle Modification for Managing Hypertension

MODIFICATION	RECOMMENDATION	APPROXIMATE BP REDUCTION, RANGE (mm Hg)
Weight reduction	Maintain normal body weight (BMI, 18.5–24.9)	5–20 per 10-kg weight loss
Adopt DASH eating plan	Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat	8–14
Dietary sodium reduction	Reduce dietary sodium intake to ≤100 mEq/L (2.4 g sodium or 6 g sodium chloride)	2–8
Physical activity	Engage in regular aerobic physical activity such as brisk walking (at least 30 min/d most days of the week)	4–9
Moderation of alcohol consumption	Limit consumption to ≤2 drinks per day [1 oz or 30 mL ethanol (e.g., 24 oz beer, 10 oz wine, or 3 oz of 80-proof whiskey)] in most men and ≤1 drink per day in women and lighter-weight persons	2–4
Adapted from Chobanian AV, Bakris GL, Cushman WC, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC VII report. JAMA 2003;289:2560, with permission.
SBP, systolic blood pressure; BMI, body mass index calculated as weight in kilograms divided by the square of height in meters; BP, blood pressure; DASH, Dietary Approaches to Stop Hypertension.
For overall cardiovascular risk reduction, stop smoking. The effects of implementing these modification are dose and time dependent and could be higher for some individuals.

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 revealing blood pressure reductions comparable to those achieved with beta-blocker or calcium-channel-blocker 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 ranks as one of the mainstays of nonpharmacologic therapy for all hypertensive patients, regardless of underlying pathophysiology, although the degree of benefit 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). Although it is clear that individuals vary in 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 do 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 low-sodium diet (2 g/d), depending on their volume status. 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

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 (TAIM) 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 middle-aged 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 will therefore reduce multiple risk factors simultaneously.

Reduction in Excess Alcohol Consumption

Epidemiologic data indicate a relationship between excess alcohol consumption and risk of hypertension. Intake of 2 oz of 100 proof whiskey, 10 oz of wine, or 24 oz of beer or more on a daily basis significantly increases the risk of becoming hypertensive. These amounts are smaller for women. Small-scale studies suggest that a daily alcohol intake of less than 1 oz may result in a modest decrease in blood pressure. Excessive alcohol intake is a frequent cause of “refractory” hypertension.

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 treatment and prevention of hypertension even without achieving weight loss. Utilizing such a diet (the DASH diet), mildly hypertensive participants in the landmark DASH study demonstrated reductions of 11.4 mm Hg in SBP and 5.5 mm Hg in DBP. The DASH diet (which is also rich in calcium, magnesium, and potassium) appears to be more effective than prescribing potassium, calcium, or magnesium supplements and demonstrates benefit across a broad spectrum of patient groups.

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 those with mild pressure elevations, but a rigorous meta-analysis 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 (6) of multiple lifestyle interventions that included the DASH diet, weight loss, exercise, and restriction of sodium and alcohol revealed significant reductions in blood pressure, both in persons with mild hypertension and those without hypertension.

Pharmacologic Therapy: Basic Issues (1,3,4,16,17,18,19,20,21,22)

When to Initiate Drug Therapy

As noted previously, treatment is guided by estimate of overall cardiovascular risk (Fig. 26.1 and Table 26.1). Persons with stage II hypertension, target-organ damage, diabetes, or multiple cardiovascular risk factors (especially diabetes) should begin 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, 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).

Figure 26-1. BP, blood pressure; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CCB, calcium-channel blocker. Algorithm for treatment of hypertension. (From Chobanian AV, Bakris GL, Cushman WC, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC VII report. JAMA 2003;289:2560, with permission.)

Elderly patients with isolated systolic hypertension have a significant risk of cardiovascular disease and should be treated. Systolic pressure is a better predictor of risk in older patients than diastolic. Clear benefit in the reduction of cardiovascular risk has been demonstrated by the Systolic Hypertension in the Elderly (SHEP) trial as well as several others.

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Goals, Efficacy, Intensity, and Duration of Treatment

As noted earlier, reducing overall cardiovascular risk to prevent heart attack and stroke requires not only reducing blood pressure, but also attending to the other cardiovascular risk factors amenable to treatment (e.g., smoking, lipids, hyperglycemia, LVH; see Chapters 27, 54, and 102). Blood pressure should be lowered to at least 140/90 mm Hg, with 135/85 mm Hg the minimum goal in persons with diabetes or overt cardiovascular disease. Those with renal insufficiency and proteinuria should ideally be brought to less than 125/80 mm Hg to slow the progression to end-stage renal disease. When following patients with home monitoring devices, home blood pressures should generally be less than 135/85 mm Hg, which takes into account any underestimates of true pressure by home readings. The so-called J-curve phenomenon (increased risk at low blood pressures) suggested harm from lowering blood pressure too much, but meta-analysis finds the harm related to underlying illness rather than to blood pressure-related events.

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 caveat that they should continue to be monitored biyearly for some time because pressures can slowly rise months after stopping therapy.

Selection of Initial Agent

Regardless of the medical regimen selected, all nonpharmacologic measures should be continued because they enhance the effectiveness of drug therapy and allow for use of fewer medications at lower doses. Selection of pharmacologic therapy for essential hypertension remains largely empiric, guided by a few generalizations about underlying mechanisms (e.g., sodium retention is common in the elderly and African Americans) and the results of major prospective trials. In the future, a more pathophysiologic approach should be possible aided by better means of detecting underlying mechanisms and important genetic polymorphisms that determine disease and drug response (e.g., α-adducin gene variant associated with salt-sensitive hypertension and response to diuretics).

In the meantime, evidence-based consensus recommendations are the best guides. JNC VII continues to recommend thiazide diuretics and beta-blockers as the preferred first-line agents in most instances for pharmacologic treatment of hypertension. In large-scale, prospective, randomized, controlled trials, these agents significantly reduce cardiovascular morbidity and mortality. All are available generically and at much-lower cost compared with other agents.

Other drugs recommended as alternative first-line agents (i.e., angiotensin-converting-enzyme inhibitors [ACEIs] and calcium-channel blockers [CCBs] have been evaluated in major long-term, large-scale, prospective, randomized head-to-head study (e.g., in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]). The thiazide-like diuretic chlorthalidone proved just as effective as ACEI therapy with lisinopril and CCB treatment with amlodipine in reducing rates of fatal coronary heart disease, nonfatal myocardial infarction, 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. ALLHAT uncovered an unappreciated increase in risk of heart failure in older men taking the previously recommended first-line alpha-blocker agent doxazocin.

Selection of Subsequent Agents

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 the 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 another first-line agent of a different class is recommended rather than adding a second agent. Although monotherapy suffices in some cases,

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most patients will require two or more medications to reach 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.

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. Thiazides and generic beta-blockers (e.g., propranolol, metoprolol, atenolol) provide the most cost-effective approach to pharmacologic therapy (Table 26.3). The reaffirmation of their primacy in randomized, prospective, head-to-head study should help to reduce the cost of treatment as reliance on the newer, more expensive antihypertensive agents diminishes over time. Especially helpful should be the cost savings from the use of thiazide diuretic therapy as a preferred first-line therapy, a practice that had been on the decline over the last decade out of concern for possible adverse metabolic effects (see later discussion). Diuretic use declined from 56% to 27% from 1982 to 1992. If the percentage of diuretic use had remained the same over that time period, $3.1 billion would have been saved. Also helping to reduce cost is the increasing availability of generic formulations of ACEIs and CCBs. 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. Antihypertensive Drugs

CLASS	DRUG	INITIAL/MAXIMUM DOSE (mg/D)	FREQUENCY	RELATIVE COST
Diuretics	Thiazide type
	Hydrochlorothiazide (generic)	12.5/50	qd/bid	1
	Esidrix			4
	Microzide			12
	Chlorthiazide (generic)	125/500	qd/bid	1.5
	Diuril			4
	Chlorthalidone (generic)	12.5/50	qd	1
	Hygroton			22
	Indapamide (generic)	1.25/5	qd	11
	Lozol			26
	Metolazone (generic)	1.25/5	qd	17
	Mykrox	0.5/1		22
	Potassium sparing
	Triamterene (Dyrenium)	50–150	qd/bid	11
	Spironolactone	12.5–100	qd/bid	10
	Aldactazide			13
	Amiloride	5–10	qd/bid	11
	Midamor			15
	Combination
	Hydrochlorothiazide 25 mg/		qd/bid	7
	triamterene 37.5 mg
	Dyazide			14
	Maxide			15
	Hydrochlorothiazide 50 mg/		qd	2
	amiloride 5 mg
	Moduretic			18
	Hydrochlorothiazide 25 mg/		qd/bid	10
	spironolactone 25 mg
	Aldactazide			14
	Loop
	Furosemide	20/320	qd/tid	1
	Lasix			5
	Ethacrynic acid (Edecrin)	25/100	qd/tid	10
	Bumetanide	0.5/5	qd/tid	4
	Torsemide (Demadex)	5–20	qd/bid	15
Beta-Blockers	Atenolol	25–100	qd/bid	1
	Tenormin			31
	Betaxolol (Kerlone)	5–40	qd	26
	Bisoprolol (Zebeta)	5–20	qd	32
	Metoprolol	50–200	qd/bid	2
	Lopressor			19
	Toprol XL	50–400	qd	16
	Nadolol	20–240	qd	14
	Corgard			36
	Propranolol	40–240	bid	1
	Inderal			32
	Inderal LA			28
	Timolol	10–40	bid	31
	Blocadren			28
Beta-Blockers with Intrinsic Sympathetic Activity	Acebutolol	200–1,200	qd/bid	24
	Sectral			35
	Carteolol	2.5–10	qd	31
	Penbutolol (Levatol)	20	qd	37
	Pindolol	10–60	bid	8
	Visken			59
Alpha–Beta-Blockers	Carvedilol (Coreg)	12.5–50	bid	92
	Labetalol (generic)	200–1,200	bid	28
	Normodyne			33
	Trandate			33
Angiotensin-Converting-Enzyme Inhibitors (ACEIs)	Benazpril (Lotensin)	10–40	qd/bid	23
	Captopril (generic)	12.5–150	bid/tid	1
	Capoten			26
	Enalapril (Vasotec)	2.5–40	qd/bid	24
	Fosinopril (Monopril)	10–40	qd/bid	26
	Lisinopril (Prinivil)	5–40	qd	26
	(Zestril)			26
	Moexipril (Univasc)	7.5–30	qd/bid	17
	Quinapril (Accupril)	5–80	qd/bid	28
	Ramipril (Altace)	1.25–20	qd/bid	22
	Trandolapril (Mavik)	1–4	qd	20
Antiotension-Receptor Antagonists	Candesartan cilexetil (Atacand)	8–32	qd	36
	Irbesartan (Avapro)	150–300	qd	36
	Losartan (Cozaar)	25–100	qd/bid	37
	Telmisartan (Micardis)	40–80	qd	38
	Valsartan (Diovan)	80–320	qd	36
	Side effects: same as ACEIs but do not cause cough
Calcium-Channel Blockers	Dihydropyridines
	Amlodipine (Norvasc)	2.5–10	qd	40
	Felodipine (Plendil)	2.5–10	qd	29
	Extended release
	Isradipine (DynaCirc CR)	5–10	qd	37
	Nicardipine (Cardene SR)	60–120	bid	40
	Nifedipine (Adalat CL)	30–90	qd	31
	(Procardia XL)			42
	Nisoldipine (Sular)	10–60	qd	27
	Nondihydropyridines	120–360	bid	48
	Diltiazem (extended release)
	Cardizem SR			54
	Cardizem CD	120–360	qd	35
	Dilacor XR	120–480	qd	35
	Diltia XT	120–480	qd	27
	Tiamate	120–480	qd	52
	Tiazac	120–480	qd	28
	Verapamil (extended release)	120–480	qd/bid	35
	Calan SR			32
	Isoptin SR			32
	Verelan			37
	Covera HS	180–480	qd	35
Alpha-Blockers^a	Prazosin (generic)	1–20	bid/tid	2
	(Minipress)			14
	Terazosin (Hytrin)	1–20	qd	51
	Doxazosin (Cardura)	1–16	qd	30
Sympatholytics (central)	Clonidine	0.1–0.6	bid/tid	1
	Catapres			20
	Catapres TTS (transdermal)	1 patch weekly 0.1–0.3		32
	Guanabenz	4–64	bid	12
	Wytensin			24
	Guafacine (Isurelim)	1–3	qd	19
	Tenex			32
	Methyldopa	250–2000	bid	4
	Aldomet			18
Sympatholytics (peripheral)	Guanethidine (Ismetlin)	10–50	qd	18
	Guanadrel (Hylorel)	10–75	bid	22
	Reserprine	0.05–01	qd	1
Vasodilator (direct)	Hydralazine	40–200	qd/bid	3
	Apresoline			30
	Minoxidil	2.5–40	qd/bid	3
	Loniten			17
Combination Preparations (selected) ACEIs/Diuretics	Benazepril 5, 10, 20 mg/HCTZ		qd	24
	6.25,12.5, or 25 mg
	quad Lotensin HCT
	Captopril 25 or 50 mg/HCTZ 15 or 25 mg		qd	22
	Capozide			28
	Enalapril 5 or 10 mg/HCTZ 12.5 or 25 mg
	Vaseretic			33
	Lisinopril 10 or 20 mg/HCTZ 12.5 or 25 mg
	Prinzide			31
	Zestoretic			29
	Moexipril 7.5 or 15 mg/HCTZ 12.5 or 25 mg
	Uniretic			17
Angiotensin	Losartan 50 or 100 mg/HCTZ 12.5 or 25 mg
II–Receptor	Hyzaar			37
Antagonists	Valsartan 80–160 mg/HCTZ 12.5 mg
and Diuretics	Diovan HCT			36
qd, daily; bid, twice daily; tid, thrice daily.
^aFirst dose at bedtime.

Pharmacologic Therapy: First-Line Agents (1,16,17,19,20,22,23,24,25,26,27,28,29,30,31,32,33,34,35)

Thiazide Diuretics

These agents are experiencing a renaissance of use as first choice for pharmacologic therapy, spurred on by the findings from ALLHAT (see prior discussion), which documented long-term outcomes equal to or better than those achieved with ACEIs or CCBs. Compared with ACEIs, CCBs, and alpha-blockers, thiazides produce comparable reductions in blood pressure and LVH, and similar or superior reductions in risks of cardiovascular morbidity and mortality. Their proven efficacy, safety, and extremely low cost make them a compelling first choice for pharmacologic management of hypertension (Table 26.3).

Mechanism of Action

Thiazides enhance sodium excretion, resulting in a reduced intravascular volume and reduced peripheral resistance (presumably by lowering intracellular sodium in vascular smooth muscle cells). Potassium excretion is increased, and uric acid and calcium excretions are decreased.

Adverse Effects

Potassium wasting is a consequence of the drug's effect on the distal tubule and is exacerbated by high salt intake. Clinically significant hypercalcemia is exceedingly rare, although a decrease in calcium excretion does occur and can be beneficial in patients with osteoporosis or calcium-containing renal stones (see Chapter 135). Hyperglycemia is usually mild and infrequent at the low doses currently recommended. Mild hyperuricemia may occur but usually not to the degree that necessitates discontinuation of therapy. A transient increase in low-density-lipoprotein (LDL) cholesterol has been noted. Thiazides may cause rash, especially a photosensitizing type, and rarely may precipitate pancreatitis. Allergy to sulfonamide antibiotics is not associated with allergy to thiazides; there is no cross-reactivity between the two classes of drugs. Most adverse metabolic effects can be minimized or eliminated by restricting dose to the equivalent of 25 mg/d or less of hydrochlorothiazide. Higher doses generally offer little increase in efficacy while increasing the likelihood of metabolic effects.

Monitoring

Checking the serum potassium regularly and correcting of even mild hypokalemia are essential in a person with underlying cardiac disease, particularly one bothered by dysrhythmias or taking digoxin (see Chapters 29 and 32). Hypokalemia can be prevented by concomitant salt restriction, increased dietary potassium, and, when necessary, the addition of potassium-sparing agents or supplements (see Chapter 32). Potassium levels should be maintained in the normal range. Severe degrees of hypokalemia may cause muscle weakness. The serum glucose requires close monitoring when thiazides are used in a diabetic, and the uric acid should be watched if the patient has clinical gout. There is no need to monitor LDL cholesterol or serum calcium.

Beta-Blockers

These agents are highly effective in reducing cardiovascular morbidity and mortality, generally well tolerated, and relatively low in cost. They provide secondary prevention following myocardial infarction and help reverse left ventricular remodeling but appear less effective in controlling blood pressure in the elderly, who should not start with a beta-blocker unless there is concurrent coronary artery disease.

Mechanism of Action

Their precise mode of blood pressure reduction remains unclear, but beta-blockers reduce cardiac output, renin and catecholamine release, central sympathetic activity, and peripheral resistance.

Adverse Effects

Side effects attributable to beta-blockade include bradycardia, fatigue, decreased exercise tolerance, and increased airway resistance. Thus, these agents should be avoided in persons with conduction-system disease and active bronchospastic conditions, but carefully selected persons with coronary disease (see Chapter 30) and heart failure (see Chapter 32) may actually benefit from their use. Beta-blockers can modestly increase insulin resistance and slightly reduce HDL cholesterol, side effects that do not seem to cancel their beneficial effects on hypertension and overall cardiovascular risk.

Anecdotal and observational data have attributed neuropsychiatric side effects (depression, sexual dysfunction, cognitive impairment) to beta-blocker use. However, prospective, randomized trials have failed to confirm these observations as well as the theory that degree of lipid solubility and central nervous system penetration might correlate with risk of neuropsychiatric side effects. In fact, failure to control blood pressure is a risk factor for dementia in older persons. Some persons report nightmares with beta-blocker use.

Preparations

All appear to be equally effective for treatment of hypertension, though differences in their cardioselectivity and intrinsic sympathomimetic activity can be used to advantage. Cardioselectivity (greater effect on β₁-adrenergic receptors of the heart than on β₂-receptors of blood vessels and bronchi) is preferred in hypertensive patients with a history of bronchospastic disease (i.e., asthma, chronic obstructive pulmonary disease). Low-dose cardioselective beta-blocker therapy is not contraindicated in such persons (see Chapter 48), but cardioselectivity is a relative quality that declines as dose increases. During exacerbations of bronchospastic disease, even cardioselective beta-blockers may not be tolerated. Atenolol and

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metoprolol are examples of the commonly used cardioselective beta-blockers.

Some beta-blockers have intrinsic sympathomimetic activity (e.g., pindolol, acebutolol, carvedilol), which cause less bradycardia and less disruption of lipid and carbohydrate metabolism. They help to maintain cardiac output with exercise, allowing cardiac conditioning. They are comparable with other beta-blockers in ability to lower blood pressure. The beta-blocker labetalol is unique in that it has both alpha- and beta-blocking actions, with about one-fourth the potency of propranolol and one-sixth the potency of phentolamine. Its rapid onset of action has made it useful for use in hypertensive emergencies—especially when given parenterally—but its chronic oral use has been limited by tendencies to cause orthostatic hypotension, sexual dysfunction, and hepatocellular injury.

Angiotensin-Converting-Enzyme Inhibitors

ACEIs are the class of choice in patients with type 1 or type 2 diabetes because of their demonstrated protective effect on the kidney. In addition, they have been shown to reduce cardiovascular mortality in patients with heart failure and in those with myocardial infarction complicated by systolic dysfunction as well as in high-risk patients without systolic dysfunction. They reverse left ventricular remodeling and hypertrophy due to hypertension.

Mechanism of Action

These drugs block the conversion of renin-activated angiotensin I to angiotensin II (ATII), a potent vasoconstrictor that also stimulates the production of aldosterone. In addition, they inhibit the breakdown of bradykinin, itself a vasodilator, which also stimulates the production of vasodilatory prostaglandins. At least some of the effects of these drugs are related to their effect on local angiotensin systems in key organs (e.g., heart and kidney). The blockade of ATII results in suppression not only of its vasoconstricting effects and its effect on aldosterone release, but also its adverse effects on myocardium and the vasculature, which facilitate vascular inflammation and impaired vasodilation.

Adverse Effects

The most troublesome side effect is an annoying dry cough that occurs in about 10% to 20% of patients. It is mostly nocturnal, described as an irritation in the throat, and believed to be linked to the effect of the drug on bradykinins. About half of patients who experience the cough find it severe enough to warrant discontinuation of the medication. Switching to another ACEI rarely solves the problem. Uncommon side effects include rash, taste disturbances, and angioedema; agranulocytosis is extremely rare and is prevalent only at very high doses.

Because the ACEIs block the production of aldosterone, they can lead to hyperkalemia when used in conjunction with a potassium-sparing diuretic, potassium supplementation, or nonsteroidal antiinflammatory drugs. Potentially fatal hyperkalemia has been reported in diabetic patients with hyporeninemic/hypoaldosteronemic hypertension. Close monitoring of the serum potassium is indicated in such situations.

ACEIs preserve renal function in hypertensive diabetics as well as in any hypertensive patient with renal insufficiency by lowering intraglomerular pressure and hence slowing the progression to end-stage renal disease. Because of this beneficial effect, creatinine may rise following the institution of ACEIs in this setting. This is not due to a toxic effect on the kidney. Up to a 35% rise in creatinine is acceptable. If creatinine rises higher than this, the ACEI should be stopped and consideration given to the possible presence of bilateral renal artery stenosis. The originally reported glomerular injury is very rare, except at the extremely high doses used in early clinical trials. However, patients with renal failure are still at risk for glomerular injury when large doses are used, necessitating careful monitoring of renal function.

The blockade of the local renin–angiotensin system in the placenta is thought to be responsible for the adverse effects these drugs have on the developing fetus, presumably by impairing placental blood flow. They are absolutely contraindicated in pregnancy.

Preparations

There are many ACEIs on the market, differing predominantly in cost and duration of action. Generic formulations of captopril and lisinopril are the least expensive (Table 26.3).

Angiotensin II–Receptor Blockers (ARBs)

This class of drugs blocks the angiotensin II receptor, thus inhibiting the vasoconstrictive effects of angiotensin II and the associated stimulation of aldosterone production. These agents have no effect on bradykinin metabolism, which probably accounts for their being free of the cough that may accompany ACEI therapy. Aside from the lack of cough, their side effects resemble those of ACEIs. Emerging data from studies in diabetics and persons with heart failure suggest ARBs are comparable to ACEIs in preserving renal function, reversing left ventricular remodeling, and lowering cardiovascular morbidity and mortality (see Chapters 32 and 102). They appear to be more effective than beta-blockers in preventing cardiovascular morbidity and death in persons without cardiovascular disease. Because of their high cost due to lack of generic availability, they should be reserved for patients intolerant to ACEIs because of cough or angioedema.

Calcium-Channel Blockers

These agents are generally well tolerated and effective in lowering blood pressure, particularly in African American patients and the elderly. ALLHAT demonstrated efficacy for the CCB amlodipine in reducing cardiovascular morbidity and mortality, but results were not as good as those achieved by use of a diuretic, especially with regard to heart failure. In addition, this class of antihypertensives has been the subject of significant controversy since publication of retrospective data suggesting an increased incidence of myocardial infarction and sudden death associated with their use. These data derive from studies of short-acting preparations (especially nifedipine and its congeners), with speculation that their rapid onset and offset of action may result in wide swings in blood pressure, increasing sympathetic tone and ultimately myocardial oxygen demand. The short-acting versions of these drugs are not recommended. There has been no indication of increased coronary morbidity in studies of long-acting CCB preparations. These drugs appear to be useful in improving glomerular filtration rate in patients with renal insufficiency; however, it remains unclear whether these agents prolong the time to dialysis. Brand-name formulations are very expensive.

Mechanism of Action

CCBs impede the entry of calcium in heart and vascular smooth muscle cells, resulting in a decreased cellular calcium concentration, which reduces vascular smooth muscle contraction and lowers peripheral resistance. These agents also have a mild natriuretic effect, making them potentially useful in patients with sodium retention (e.g., the

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elderly and African Americans). None adversely affects lipids or insulin sensitivity, and all reduce LVH.

Adverse Effects of Individual CCBs

There is considerable variation in action and side effects among the CCBs.

Amlodipine

Amlodipine is among the most widely prescribed of the CCBs, superseding many of the earlier agents in this class because it produces less reflex tachycardia and less negative inotropy. Peripheral edema occurs (and can be substantial in persons with preexisting venous insufficiency), but usually to a lesser degree than with vasodilating CCBs. Amlodipine is comparable to thiazide diuretic therapy in achieving most major endpoints, except for being associated with a slightly higher rate of heart failure in high-risk hypertensive patients.

Nifedipine

Nifedipine and its dihydropyridine congeners (e.g., nicardipine, isradipine, felodipine) are potent vasodilators that manifest negative inotropic effects in vitro, but clinically cause little net reduction in cardiac output. Their main drawbacks are reflex tachycardia and peripheral edema secondary to vasodilation. As noted earlier, retrospective study suggests increased risk of myocardial infarction and cardiac sudden death associated with use of the short-acting dihydropyridine formulations, which are known to trigger reflex sympathetic activation. Occasionally, headache and flushing may be troublesome. In a small number of patients, esophageal reflux can become a problem secondary to relaxation of the lower esophageal sphincter.

Verapamil

Verapamil is available generically at low cost. Its main disadvantages are negative inotropy and conduction-system disturbances, leading to arterioventicular (AV) nodal block and bradycardia; the drug should not be used in patients with heart failure or suspected conduction-system disease. On the other hand, it is very useful for rate control in patients with hypertension in the setting of atrial fibrillation with a rapid ventricular response rate. Leg edema is usually not a problem unless heart failure worsens, but constipation, headache, and dizziness can be problematic.

Diltiazem

Diltiazem falls between nifedipine and verapamil, having mildly negative net effects on inotropy and conduction, but is less likely than nifedipine to cause leg edema. Efficacy is enhanced by addition of a small dose of thiazide diuretic. The drug can cause some AV nodal block and should not be used in the setting of bradycardia.

Alpha-Blockers

These drugs act peripherally at vascular postsynaptic α-adrenergic receptors, causing arteriolar and venous dilation. Because they affect both the arterial and venous systems, they cause less reflex tachycardia than pure arterial vasodilators (see later discussion). They help to reverse left ventricular remodeling. Their use as a first-line drug in older hypertensive men with concurrent prostatism has been popular because they provide symptomatic relief of obstructive urinary symptoms (see Chapter 138), but the finding of a significant increase in risk of heart failure associated with alpha-blocker (doxazosin) use among such men in the ALLHAT study has removed this class from the list of first-line drugs. Risk is attenuated but not eliminated with concurrent use of an additional first-line agent to ensure achievement of target blood pressure.

The principle side effect of alpha-blocker therapy is postural hypotension, most prominent with use of older alpha-blockers (e.g., prazosin, terazosin) in elderly patients and those taking diuretics. Such patients could experience profound postural hypotension leading to syncope 1 to 3 hours after the initial dose, necessitating starting with a low dose at bedtime and staying supine for at least 3 hours. The newer, longer-acting preparations (e.g., doxazosin) are less likely to cause first-dose syncope; however, even with doxazosin, postural lightheadedness is still a problem, affecting about one-fifth of patients and becoming more likely as dose exceeds 1 mg/d.

Alpha-blockers have no adverse effects on lipids; in fact, they slightly raise HDL cholesterol and modestly reduce LDL (both on the order of 3% to 5%). Recommendations as to how these agents should be used in combination with other-first line agents await further study.

Combination Therapy

Almost all of the classes of first-line drugs mentioned earlier may be used in combination to enhance blood pressure control. Especially effective is adding a thiazide diuretic to a nonthiazide monotherapy program; even small doses (e.g., 12.5 to 25 mg/d of hydrochlorthiazide) can be very helpful. Adding an ARB to ACEI monotherapy can enhance reduction in blood pressure, but adding a thiazide provides similar benefit and at much lower cost. Caution should be used when combining verapamil and a beta-blocker in a person with underlying heart disease because of their additive suppressive effects on left ventricular function.

Pharmacologic Therapy: Second-Line Agents

The second-line agents are worth considering when the list of first-line agents has been exhausted; however, most have features that make them less desirable, and in most instances, control can be achieved with combination use of first-line drugs. Consequently, they should not take precedence over a first-line drug. Second-line agents are generally reserved for patients who are refractory to combinations of first-line agents or who have special underlying conditions such as renal failure. They include the loop diuretics, distal tubular diuretics, centrally acting sympatholytics, and the older peripheral vasodilators (Table 26.3).

Loop and Potassium-Sparing Diuretics

Loop diuretics (furosemide, ethacrynic acid, bumetanide are reserved for patients with evidence of renal insufficiency (creatinine clearance <30% of normal) or with allergy to thiazides. They are typically used in conjunction with minoxidil (see later discussion).

Distal tubular diuretics (e.g., spironolactone, triamterene, amiloride) are weak antihypertensive agents used predominantly in combination with thiazides to spare potassium loss. The combination preparations are widely promoted, but it is best to avoid starting with such a fixed combination until the necessary thiazide dose has been established. Hypertensive patients who must avoid hypokalemia (e.g., those taking digitalis, experiencing ventricular irritability, or suffering from organic heart disease) are the best candidates. Other indications are mineralocorticoid hypertension, thiazide hypersensitivity, and severe gout. These drugs must be used with extreme caution in patients with renal insufficiency, ACEI use, or insulin-dependent diabetes with renin deficiency, where risk of serious hyperkalemia is substantial. The tendency of spironolactone to cause gynecomastia limits its use in hypertension to patients with primary hyperaldosteronism. A new, selective aldosterone antagonist, elprenolone, has been approved for congestive heart failure; approval for use in hypertension is pending,

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It shows promise when combined with a thiazide in salt-sensitive hypertensives.

Centrally Acting Sympatholytics

Methyldopa, clonidine, and guanabenz are centrally acting sympatholytics that reduce blood pressure by stimulating central α-adrenergic receptors, which in turn reduce sympathetic outflow to the heart and vasculature. Because they cause secondary sodium retention and generally require the use of a diuretic, they should be considered as second-line agents. Although all these agents frequently cause drowsiness, fatigue, and impotence, lower doses are often quite well tolerated, even in the elderly. Methyldopa occasionally causes fever, acute or chronic hepatitis, and a Coombs-positive hemolytic anemia. Clonidine (and sometimes methyldopa) are more likely to cause sedation, dry mouth, and rebound hypertension with abrupt cessation of therapy. A slow-release transdermal clonidine patch is available and convenient but very expensive and commonly irritating to the skin. Low-dose clonidine (0.1 mg) given as a once-daily dose before bed is well tolerated in the elderly. Guanabenz and guanfacine are similar to clonidine in action and side effects.

Reserpine is one of the oldest antihypertensive agents, acting as a postganglionic adrenergic antagonist. Its advantages are low cost, good efficacy, and once-daily dose. Significant side effects include severe depression, nightmares, drowsiness, nasal congestion, gastrointestinal disturbances, and bradycardia.

Older Arterial Vasodilators

These drugs are rarely used because of the availability of better tolerated and more effective agents. The older arterial vasodilators (e.g., hydralazine, minoxidil) act directly to relax arterial smooth muscle. Disadvantages include reflex tachycardia, sodium and water retention, and short duration of action, necessitating frequent dosing. Hydralazine is typically used as a third-line agent in combination with a beta-blocker and a diuretic agent. It can cause headache, dizziness, and a lupus-like syndrome, especially in doses exceeding 200 mg/d. Reflex tachycardia may exacerbate angina. Minoxidil is an extremely potent vasodilator and should be used only in patients with moderately severe hypertension uncontrolled by other medications (see later discussion). Both a beta-blocker and a loop diuretic must be used with it. Salt and water retention may be marked, requiring high doses of furosemide. Hypertrichosis is common and has led to the drug's topical use for hair loss. Rare adverse effects include pericardial effusion and even cardiac tamponade.

Special Situations (1,4,36,37,38,39,40,41,42,43,44)

Refractory Hypertension

Patients are considered refractory if they fail to achieve target blood pressure reductions despite full doses of a three-drug regimen.

Etiologies

The most common causes are poor compliance, alcohol excess, and obesity. In addition, blood pressure becomes increasingly difficult to control in the presence of deteriorating renal function, a time when it is crucial to lower blood pressure to the lower than usual goal of less than 125/80 mm Hg to prolong the time to need for dialysis for as long as possible. This may require three to five medications and the assistance of a nephrologist. Other etiologies include renovascular disease and other secondary causes of hypertension (see Chapter 19).

Use of over-the-counter decongestants containing sympathomimetics, nonsteroidal antiinflammatory agents, and exogenous estrogens is among the pharmacologic causes. At times, the cause is a treatment regimen that contains an irrational combination, such as two agents within the same class, or an inadequate amount of diuretic for the degree of salt intake and sodium retention present.

Occasionally, the cause is pseudo-refractoriness due to the anxiety of the office visit (so-called “white-coat” hypertension) or to a marked vasoconstrictor response to blood pressure determination performed with an arm cuff. In the former, the act of taking the blood pressure produces a rise predominantly in the systolic blood pressure; in the latter, the rise is predominantly in the diastolic pressure (see Chapter 19).

Assessment

Medication compliance, weight gain, salt and alcohol excess, and use of other drugs should be observed. Pill counts are the best compliance check. A history of nocturia or ankle edema is suggestive of volume overload from excessive salt intake or deterioration of cardiac or renal function. History and physical examination are performed to check for signs of secondary etiologies (see Chapter 19), target-organ damage, and volume overload. If white-coat hypertension is suspected, blood pressures should be taken by the patient at home and at work, after checking the patient's technique in the office. Continuous ambulatory monitoring may also be of use in this situation (see Chapter 19). However, even if a pseudo-refractory etiology is suspected, it should not be grounds for truncating a workup for end-organ damage. Even white-coat hypertension is associated with an increased risk of LVH and diastolic dysfunction.

If there is no clinical evidence of a secondary cause, then a check of the serum sodium, potassium, blood urea nitrogen, creatinine, and urinalysis should suffice for evidence of renal injury. The echocardiogram, a sensitive measure of cardiac target-organ effects, can also help differentiate between true refractoriness leading to target-organ damage and pseudorefractoriness.

Empiric Therapy

If workup fails to reveal a definite cause, the patient should be placed on a 2-g/d sodium/reduced-calorie diet, restricted to 1 oz of alcohol per day, and prescribed an exercise program. A maximal three-drug regimen should be continued (including an adequate diuretic dose). The patient is instructed to monitor pressure at home and should be followed closely. If these measures fail, then before escalating the medication program, one should consider consultation with a hypertension specialist for further consideration of possible causes (e.g., renal artery stenosis; see Chapter 19). Patients who are truly refractory yet free of a serious underlying etiology may respond to the combination of minoxidil, a loop diuretic, and a beta-blocker. Patients with refractory hypertension believed due to white-coat response should be followed closely. Those who manifest target-organ changes should be treated like any other hypertensives. Those who do not show any target-organ changes should be watched for the development of such changes and, in the meantime, be prescribed a program of diet and exercise.

Treatment of Renal Artery Hypertension

Renal artery hypertension due to atherosclerotic disease is an important cause of difficult-to-control hypertension in the elderly. The advent of noninvasive imaging studies has facilitated identification. Although revascularization might be necessary both for control of blood pressure and preservation of renal function, long-term

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observational studies in elderly persons with moderately severe stenosis find a surprisingly good renal prognosis with conservative therapy (medication only). Nevertheless, overall mortality risk in this group of patients is high due to high prevalence of underlying cardiovascular disease. Randomized trial of angioplasty compared with drug therapy finds no significant difference in outcomes. Although revascularization by angioplasty is of acceptable risk when done by experienced operators, it does not appear to offer any advantages in terms of blood pressure control or renal function over initial medical therapy. Hypertensive patients with atherosclerotic renal artery stenosis should be followed closely and treated initially with antihypertensive medication. Those who fail medical therapy due to grossly inadequate blood pressure control or worsening of renal function are reasonable candidates for consideration of revascularization, especially if hypertension is complicated by flash pulmonary edema, high-serum creatinine with bilateral disease, or very tight stenosis.

Hypertension Associated with Estrogen Use

Hypertension occurs rarely in young women on oral contraceptives since the advent of low-dose estrogen pills. There is no evidence that hormone replacement therapy causes an elevation in blood pressure, and these drugs may be used in the hypertensive patient to treat disabling menopausal symptoms.

Hypertension in Pregnancy

Hypertension that develops during pregnancy may represent either preexisting hypertension or preeclampsia.

Preexisting Hypertension

Pressure elevations that appear before 20 weeks are almost always due to preexisting disease. Some preexisting hypertension improves during pregnancy because of the hemodynamic changes that occur at this time. Such patients may terminate therapy for the duration of their pregnancy, but pressures should be followed closely, as should the urinalysis for early development of proteinuria (a powerful predictor of adverse outcomes). Others require continuation of treatment. The goal of lowering blood pressure in those with preexisting disease is the safety of the mother. There is no fetal benefit to blood pressure reduction; antihypertensive drugs do not cure or reverse preeclampsia.

The usual threshold for initiating antihypertensive medication is a DBP exceeding 100 mm Hg. For DBPs between 90 and 100 mg Hg, modest sodium restriction and increased rest often suffice. If they do not, and blood pressure continues to rise, then beginning methyldopa, a beta-blocker, or hydralazine is safe and effective in pregnancy. ACEIs are contraindicated due to the dependence of placental blood flow on the intrauterine renin–angiotensin system. Diuretics are generally avoided during pregnancy. Beta-blockers, calcium-channel blockers, and alpha-blockers may be used, though guidelines await further study.

Preeclampsia

Blood pressure of 140/90 mm Hg or higher, edema, and proteinuria all appear in the third trimester. The typical patient is a very young primagravida, but multiple births, diabetes, and hydatidiform mole contribute to risk. Change of partner is not a risk factor, but prolongation of interval between pregnancies is. At 17 to 20 weeks of gestation, a resting blood pressure of greater than 110/75 mm Hg (sitting) or greater than 100/65 mm Hg (left lateral decubitus position) suggests an increased risk of developing preeclampsia because normally the pressure is lower at this time of pregnancy. If DBP rises above 90 mm Hg, bedrest is initiated and hospitalization considered.

Most antihypertensive medications safe for use in pregnancy are appropriate for treatment of preeclampsia. Low-dose aspirin does not prevent preeclampsia. Nitroprusside is given in severe cases that require hospitalization. The use of volume expansion remains controversial. Diuretics and salt restriction are to be avoided because these patients usually are intravascularly volume constricted. Such treatment might aggravate the condition by further stimulating the renin–angiotensin–aldosterone axis. Magnesium sulfate is the treatment of choice for prevention of seizures associated with eclampsia. In randomized trial, magnesium sulfate was superior to the CCB nimodipine for prevention of eclampsia.

Hypertension in the Elderly

Isolated systolic hypertension (SBP >140 mm Hg), a common finding in the elderly, significantly increases the risk of cardiovascular morbidity and mortality in persons older then the age of 65 years. In fact, SBP is among the most powerful predictors; treatment lowers the risk. The goals of therapy are to reduce SBP to less than 140 mm Hg and DBP to less than 90 mm Hg.

Nonpharmacologic Therapy

The elderly tend to have low-renin volume-overload hypertension and exhibit considerable sensitivity to salt intake. For those with very modest pressure elevations, one can begin with salt restriction, a gentle exercise program, and weight reduction if overweight. Many elderly patients respond well to a 2-g/d low-sodium diet. Reduction of excess alcohol intake to no more than 1 oz/d is also important and occasionally overlooked. Nonpharmacologic measures can lower pressure by as much as 10 mm Hg.

Pharmacologic Therapy

When drug treatment is necessary, a thiazide diuretic is the drug of choice for initial therapy. It is best to start with a low dose (e.g., hydrochlorothiazide 12.5 to 25.0 mg/d) and increase dose gradually. Increments should be small to avoid rapid lowering of pressure and postural hypotension, which can lead to lightheadedness and falls. In general, the elderly do not tolerate aggressive diuretic therapy or beta-blockers as well as younger patients. A review of 10 beta-blocker trials in the elderly found their use often failed to achieve adequate control or reductions in cardiovascular risk.

ACEIs are a reasonable consideration as initial therapy in elderly men. In randomized trial of initial antihypertensive therapy in elderly patients, ACEI actually proved superior to thiazides. Other drugs likely to cause marked postural hypotension (e.g., alpha-blockers) or daytime sedation (centrally acting sympatholytic agents, e.g., methyldopa, clonidine) are also less desirable. Cardiovascular risk reduction with use of calcium-channel blockers has been demonstrated in elderly diabetics with systolic hypertension; results in nondiabetics are less impressive.

The African American Patient

Hypertension is more prevalent in African Americans (38.2%), more commonly of the low-renin salt-sensitive variety, and more likely to be accompanied by target-organ damage than in whites. The high prevalence of obesity, smoking, and salt excess contribute, as does decreased access to medical care. African Americans show three times the risk of developing renal insufficiency, even when treated. They respond particularly well to thiazides, sodium restriction,

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weight loss, and smoking cessation. Most patients require combination therapy for adequate control. Calcium-channel blockers are effective, though their use greatly increases cost of treatment, which, in turn, might compromise long-term compliance. ACEIs and beta-blockers are somewhat less effective, perhaps because of the low-renin physiology prevalent in this population. However, they should be used in situations in which their efficacy has been established, such as the use of ACEIs in diabetic patients or beta-blockers following a myocardial infarction. Higher doses may be required to achieve the desired effect.

The Diabetic Patient

Control of hypertension is particularly important in diabetics because the risks of stroke, cardiovascular disease, and renal failure are particularly high. Blood pressure should be brought to levels below 135/85 mm Hg. ACEIs are the class of choice because they decrease proteinuria and slow the progression of diabetic nephropathy. ARBs have much the same benefits as ACEIs and should be used in patients who are intolerant of ACEIs because of cough. Calcium-channel blockers also may be protective of the kidney and are tolerated and effective, demonstrating decreases in cardiovascular risk in elderly diabetics with systolic hypertension. Although thiazide diuretics may slightly worsen glucose intolerance and hyperlipidemia, these adverse effects can be minimized or avoided by using small doses (e.g., 12.5 to 25 mg/d of hydrochlorothiazide). Beta-blockers are not contraindicated in patients taking insulin, but a relatively cardioselective preparation (e.g., atenolol or metoprolol) is preferred because it is less likely to mask catecholamine-induced hypoglycemic symptoms.

The Patient with Chronic Renal Failure

Hypertension can lead to renal injury and exacerbate it. Blood pressure control is essential to preservation of renal function in persons with chronic renal failure, partcicularly those with diabetic nephropathy (see Chapter 102). However, acute lowering of elevated blood pressure, especially to the recommended level of less than 125/80 mm Hg for persons with renal failure, can result in an acute nonprogressive increase in serum creatinine. This rise in serum creatinine is hemodynamic in orgin (a consequence of reduction in intraglomerular pressure) and independent of type of antihypertensive agent used. It is not a manifestation of drug-induced renal injury nor an indication to cut back on antihypertensive therapy (a common mistake in treatment of hypertension in chronic renal failure).

Choice of Agents

Adequate control of blood pressure in persons with chronic renal failure may require a multidrug regimen. ACEIs and ARBs effectively lower blood pressure, reduce proteinuria, and help preserve renal function. They are contraindicated when the cause of renal dysfunction is significant bilateral renal artery stenosis (>70% occlusion) and should be temporarily reduced in dose or held in the setting of acute severe volume depletion, where they may exacerbate reduction in glomerular filtration. Caution is also required when these agents are prescribed in the setting of hyperkalemia, but adding a low dose of a thiazide or loop diuretic can help minimize risk of hyperkalemia and helps treat any associated volume retention. When the serum creatinine rises above 2.5 mg/dL, sodium retention occurs, which can lead to exacerbation of blood pressure. Furosemide and/or metolazone can help counter this sodium retention and reduce blood pressure. Use of potent diuretic therapy in conjunction with an ACEI or an ARB in renal failure requires careful attention to volume status; excessive diuresis can worsen renal function.

Beta-blockers and calcium-channel blockers are also effective and can be added to the antihypertensive program. Beta-blockers have no adverse effect on renal hemodynamics or glomerular filtration, but dihydropyridine calcium-channel blockers may blunt intrarenal vascular autoregulation. Nondihydropyridine calcium-channel blockers exert a beneficial effect on renal function that is enhanced when used in combination with an ACEI or an ARB; dihydropyridine use in renal failure is reasonable if combined with ACEI or ARB therapy. Vasodilators such as minoxidil, in combination with a loop diuretic and a beta-blocker, may be necessary in refractory cases.

Other Measures

A reduced-protein diet (40 to 45 g/d) and salt restriction (2 g/d) help preserve renal function and control of blood pressure. Careful review of all other medications is essential (including over-the-counter agents); all nonsteroidal antiinflammatory drugs should be eliminated because their inhibition of prostaglandins can adversely affect intrarenal hemodynamics, compromise renal function, and impair potassium excretion.

The Stroke Patient

Control of hypertension reduces the risk of recurrent stroke. The main pitfalls of treatment are reductions in pressure that are too rapid or too vigorous, leading to cerebral hypoperfusion. Gradual gentle pressure reductions that preserve central nervous system perfusion and avoid postural hypotension are the objective.

PATIENT EDUCATION

Patient education is essential to ensuring compliance. Because it is a silent condition, hypertension does not always command the full attention of patients. High cost of medication, high frequency of doses, and drug side effects further compromise compliance. Nonetheless, some educational and behavioral efforts can enhance patient cooperation. Educationally, one needs to review the cardiovascular consequences of untreated hypertension and the ability of treatment to greatly reduce risk. Knowledge of the importance of nonpharmacologic measures is also critical and reassuring to many. That weight reduction, smoking cessation, and decrease in sodium intake may allow reduction or even elimination of antihypertensive medication can serve as a powerful motivating force.

One of the best approaches to improving compliance is to have the patient monitor blood pressure at home. Teaching the patient to perform home blood pressure determinations can foster considerable interest in blood pressure control, greatly stimulate adherence to a treatment program, and contribute to improved control. Effective home monitoring may even decrease the need for some office visits.

Medication side effects need to be addressed. Sexual dysfunction, fatigue, and depression have long bothered hypertensive patients who require drug therapy and lead many to stop their medication, often without notifying the physician. It is essential to specifically inquire about potential side effects, including symptoms of sexual dysfunction (see Chapter 229) and depression (see Chapter 227) before and after initiation of a medical regimen and to incorporate the findings into design of

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the patient's program. Patients may be reluctant to raise these issues. Use of a medication that does not interfere with sexual capacity or mental function (e.g., an ACEI such as captopril) may be indicated (see prior discussion).

INDICATIONS FOR REFERRAL AND ADMISSION

Immediate hospitalization is indicated for patients with evidence of malignant hypertension (DBP >130 mm Hg, retinal hemorrhages, papilledema, mental status changes, heart failure). Referral may be useful for patients with refractory hypertension of unknown etiology (see prior discussion), a suspected secondary cause, or worsening renal failure in the setting of adequate control.

THERAPEUTIC RECOMMENDATIONS (FIG. 26-1 AND TABLES 26.1, 26.2, 26.3) (1)

For All Patients (Fig. 26-1)

Prescribe a no-added-salt diet (2 to 3 g/d) that is low in saturated fat and rich in fruits, vegetables, and low-fat dairy products; consider greater sodium restriction in persons likely to have volume-overload hypertension (e.g., African Americans, the elderly).
Advise weight reduction (especially if >15% above ideal weight).
Limit alcohol intake to 1 oz/d.
Insist on complete smoking cessation (see Chapter 54).
Prescribe an exercise program (see Chapter 18).

For Patients with Stage 1 Hypertension (DBP 90 to 99 mm Hg, SBP 140 to 159 mm Hg), No Additional Cardiovascular Risk Factors, and No Signs of Target-Organ Disease (Fig. 26-1, and Tables 26.1 and 26.2)

Institute full nonpharmacologic measures.
Repeat blood pressure determinations regularly over the next 6 months.
If improvement is noted (DBP <90 mm Hg, SBP <140 mm Hg), then continue nonpharmacologic measures and monitor blood pressure every 3 months.
If there is no improvement after 6 to 12 months of nonpharmacologic therapy or if it fails to lower the blood pressure (DBP <90 mm Hg, SBP <140 mm Hg), then add a first-line antihypertensive agent to the nonpharmacologic program, starting with either a thiazide (e.g., hydrochlorothiazide [HCTZ] 25 mg/d) or a generic formulation of a beta-blocker (e.g., atenolol 25 mg/d).

For Patients with Stage 1 Hypertension and Additional Cardiovascular Risk Factors or Signs of Target-Organ Disease (Fig. 26-1 and Table 26.1)

Immediately institute a full nonpharmacologic program.
Repeat blood pressure determinations regularly over 3 months.
If blood pressure is not normalized after 3 months, then add first-line antihypertensive therapy (thiazide or beta-blocker; see prior discussion) to the nonpharmacologic program.

For Patients with Stage 2 Hypertension (DBP ≤100 mm Hg, SBP ≥160 mm Hg), Especially if Accompanied by Cardiovascular Risk Factors or Target-Organ Damage

Immediately institute a full nonpharmacologic program.
If blood pressure is not normalized after 1 to 2 months, then add a first-line antihypertensive therapy (see prior discussion) to the nonpharmacologic program and advance the pharmacologic program as needed.
Monitor blood pressure closely.

Initiation and Advancement of Pharmacologic Therapy

Begin pharmacologic therapy with a first-line agent, preferably a diuretic or a beta-blocker.
Choose an agent based on consideration of the patient's overall clinical situation (see later discussion), and start with a modest dose. In most cases, this will be a thiazide diuretic (e.g., HCTZ 12.5 to 25 mg/d).
If pressure is not at goal within 1 month of initiating drug therapy, either increase the dose (e.g., to HCTZ 25 mg/d if 12.5 mg is used initially) or add a second first-line agent, and recheck in 4 weeks.
If there is no response despite increasing dose, then switch to another first-line drug from a different class (e.g., a generic formulation of a beta-blocker, such as atenolol, 25 mg/d).
If there is only a partial response, then the choice is either to further increase the dose or to add a low dose of another first-line drug from a different class (e.g., add HCTZ 12.5 to 25 mg/d or a beta-blocker).
Once pressure normalizes, recheck blood pressure at 3- to 6-month intervals. When stability has been confirmed and sodium and potassium levels and renal function are stable, pressures can safely be rechecked every 6 months unless other complication factors are present.
If a two-drug regimen using two first-line agents from different classes does not suffice, select a third drug from a new class. A particularly effective three-drug regimen is an ACEI, a thiazide diuretic, and a beta-blocker.
Consider a sustained-release formulation if it is likely to increase compliance and reduce the cost of a daily program.

First-Line Agents for Initial Use

Thiazides. Consider for almost all patients. They are especially useful in those likely to have volume-overload hypertension (e.g., the elderly, African Americans, persons with nocturia or leg edema); they provide effective low-cost therapy and enhance the antihypertensive effects of beta-blockers, calcium-channel blockers, and ACEIs. Limit doses to modest amounts (e.g., HCTZ 12.5 to 25 mg/d) to minimize adverse metabolic effects, particularly in patients with marked hypercholesterolemia, poorly controlled diabetes, symptomatic gout, cardiac arrhythmias, or severe underlying coronary disease. Regularly monitor serum potassium, especially in persons with underlying heart disease.
Beta-Blockers. Consider for most patients. They are preferred in those with concurrent coronary artery disease or high
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cardiovascular risk; they are not as effective or as well tolerated in the elderly. They are among the most cost-effective. Choose a relatively cardioselective preparation (e.g., atenolol or metoprolol). Prescribe generic formulations (e.g., metoprolol, atenolol) to keep costs low. Avoid in patients with severe bronchospasm or nonischemic heart failure. Add a small dose of thiazide if fluid retention develops or if enhanced pressure control is desired.
ACEIs. Consider as the initial drug of choice for the treatment of hypertension in those with diabetes, heart failure with systolic dysfunction, or underlying coronary heart disease. They are also useful in those with volume overload, underlying sexual dysfunction, depression, and intolerance to central nervous system effects of other antihypertensive agents. May be used alone or in combination with a diuretic or a beta-blocker, which enhance their effectiveness; contraindicated in pregnancy, bilateral renal artery stenosis, and renal failure. Monitor renal function and serum potassium, especially in those with underlying renal dysfunction. Prescribe generic formulations (captopril, lisinopril) to minimize cost.
Calcium-Channel Blockers. Consider as an alternative to thiazides and ACEIs in patients with volume-overload hypertension (e.g., the elderly, African Americans) and in diabetics. Short-acting preparations should not be used because of concerns about increased risk of myocardial infarction and cardiac sudden death. Use cautiously in patients with conduction defects, especially if they are already taking a beta-blocker. Avoid if possible in patients bothered by peripheral edema; short-acting agents are contraindicated in heart failure. If there use is unavoidable, consider an agent with the least adverse peripheral vascular and cardiovascular effects (e.g., amlodipine).

ANNOTATED BIBLIOGRAPHY

1. Chobanian AV, Bakris GL, Cushman WC, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC VII report. JAMA 2003;289:2560. (The latest version of this major consensus report.)

2. Blacher J, Staessen JA, Girerd X, et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med 2000;160:1205. (Evidence of high pulse pressure as a marker of significant increase in cardiovascular risk in the elderly.)

3. Neaton JD, Grimm RH, Prineas RJ, et al. Treatment of Mild Hypertension Study. JAMA 1993;270:713. (Landmark study demonstrating benefits to major outcomes.)

4. Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991;265:3255. (Treatment of isolated systolic hypertension reduced the risk of stroke in the elderly.)

5. Boutitie F, Gueyffier F, Pocock S, et al. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 2002;136:438. (Meta-analysis; risk increases at low pressures due to underlying illness, not from lowering of blood pressure.)

6. Appel LJ, Champagne CM, Harsha DW, et al. Writing Group of the PREMIER Collaborative Research Group. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003;289:2083. (Randomized, controlled trial comparing intensive behavioral intervention [Dietary Approches to Stop Hypertension—DASH—diet and lifestyle changes] against advice only in persons with prehypertension; a significant reduction in blood pressure was achieved.)

7. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117. (A randomized trial in normotensive and mildly hypertensive patients; a diet rich in vegetables and fruits and low in saturated fat can significantly reduce blood pressure.)

8. Eisenberg DM, Delbanco TL, Berkey CS, et al. Cognitive behavioral techniques for hypertension: are they effective? Ann Intern Med 1993;118:964. (A meta-analysis incorporating data from the limited number of available well-designed studies; found no benefit over placebo.)

9. Kelemen MH, Effron MB, Valenti SA, et al. Exercise training combined with antihypertensive drug therapy. JAMA 1990;263:2766. (Exercise was just as effective as drug therapy and obviated the need for medication in mildly hypertensive patients.)

10. MacMahon SW, Norton RN. Alcohol and hypertension. Ann Intern Med 1986;105:124. (An editorial summarizing the evidence linking the two conditions and recommending a limit of <2oz/d.)

11. National High Blood Pressure Education Program Working Group. Report on primary prevention of hypertension. Arch Intern Med 1993;153;186. (Major review of nonpharmacologic measures; 327 references.)

12. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 2001;344:3. (Major randomized, controlled trial of dietary therapy.)

13. Vollmer WM, Sacks FM, Ard J, et al. Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-Sodium Trial. Ann Intern Med 2001;135:1019. (The DASH diet was effective across diverse subgroups.)

14. Wassertheil-Smoller S, Oberman A, Blaufox MD, et al. The Trial of Antihypertensive Interventions and Management (TAIM) study. Am J Hypertens 1992;5:37. (Trial demonstrating the benefit of weight loss in the control of blood pressure.)

15. Writing Group of the Premier Collaborative Research Group. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003;289:2083. (Randomized trial; lifestyle modification works.)

16. Davis BR, Cutler JA, Furberg, et al. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the ALLHAT trial. Ann Intern Med 2002;137:313. (Heart failure risk with doxazosin is attenuated but not eliminated by adding other antihypertensive agents.)

17. Psaty BM, Lumly T, Furberg CD, et al. Health outcomes associated with antihypertensive therapies used as first line agents. JAMA 2003;289:2534. (Meta-analysis of numerous trials demonstrating the benefits of low-dose diuretic therapy.)

18. Psaty BM, Smith NL, Heckbert SR, et al. Diuretic therapy, the α-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA 2002;287:1680. (Case–control study examining the relation of genetic polymorphism to response to treatment.)

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19. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981. (Major randomized, controlled trial; thiazides were found to be superior to angiotensin-converting-enzyme inhibitors [ACEIs] and calcium-channel blockers [CCBs] as initial choice of agent for the treatment of hypertension in high-risk patients (i.e., age >55 years, one or more additional cardiovascular disease risk factors.)

20. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs. chlorthalidone: the Anti-hypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLTHAT). JAMA 2000;283:1967. (Major randomized, prospective, controlled trial; compared with other first-line agents studied, doxazosin fails to reduce congestive heart failure risk.)

21. Schmieder RE, Rockstroh JK, Messerli FZ. Antihypertensive therapy: to stop or not to stop? JAMA 1991;265:1566. (A review of the evidence for cessation of therapy; 80 references.)

22. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583 (Report of the Second National Australian Blood Pressure Trial, suggesting that ACEIs were superior in preventing cardiovascular disease to diuretics in elderly men but not in women.)

23. Strom BJ, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. N Engl J Med 2003;349:1628. (Prospective cohort study; no risk of cross-allergic reaction was found.)

24. Dimsdale JE, Newton RP, Joist T. Neuropsychological side effects of beta-blockers. Arch Intern Med 1989;149:514. (A review of 55 studies on the issue, concluding there is little evidence for a difference in central nervous system effects of the lipophilic and lipophobic preparations.)

25. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first line therapy for hypertension in the elderly? JAMA 1998;279:1903. (Evidence that the answer is probably not.)

26. Perez-Stable EJ, Halliday R, Gardiner PS, et al. The effects of propranolol on cognitive function and quality of life: a randomized trial among patients with diastolic hypertension. Am J Med 2000;108:359. (No adverse effects were found.)

27. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456. (Demonstrates the protective effect of ACEIs on renal function in hypertensive diabetics.)

28. Thurman JM, Schrier RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney. Am J Med 2003;114:588. (Useful review; 85 references.)

29. Jafar TH, Schmid CH, Landa M, et al. Angiotensin converting enzyme inhibitors and progression of non-diabetic renal disease. Ann Intern Med 2001;135:73. (The protective renal effect of ACEIs extends to hypertensive nondiabetic patients with renal dysfunction.)

30. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992;327:669. (Landmark study finding reductions in morbidity and mortality.)

31. The Heart Outcomes Prevention/Evaluation Study Investigators. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Eng J Med 2000:342:1459. (Major trial further demonstrating the benefits of ACEIs in high-risk cardiovascular patients.)

32. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med 1996;334:1649. (Excellent review of the mechanism of action of this class of antihypertensive.)

33. Lacourciere Y, Belanger A, Godin C, et al. Long term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kid Int 2000;58:762. (Demonstration of similar renoprotective effects between ACEIs and angiotensin-receptor blockers.)

34. Abernathy DR, Schwartz JB. Drug therapy: calcium antagonist drugs. N Engl J Med 1999;341:1447. (Excellent review.)

35. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620. (Report from the Puget Sound Health Co-operative on the increase in myocardial infarction in patients treated with short-acting CCBs.)

36. Ritz E, Mann JFE. Renal angioplasty for lowering blood pressure. N Engl J Med 2000;342:1042. (Editorial; summarizes available data, finding little benefit over medical therapy, except in limited situations.)

37. van Jaarsveld BC, Krijnen P, Pieterman H, et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. N Engl J Med 2000;342:1007. (Randomized trial; angioplasty was no better than medical therapy.)

38. Staessen JA, Thijs L, Birkenhager WH, et al. Update on the Systolic Hypertension in Europe (Sys-Eur) Trial. Hypertension 1999;33:1476. (Major European trial; treatment of systolic hypertension reduces cardiovascular risk.)

39. Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:483. (Starting with ACEI rather than thiazide diuretic resulted in a better outcome in men.)

40. Belfort MA, Anthony J, Saade GR, et al. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med 2003;348:304. (Randomized trial; magnesium sulfate was better.)

41. Cunningham FG, Lindheimer MD. Hypertension in pregnancy. N Engl J Med 1992;326:927. (A still-useful review; 61 references.)

42. National High Blood Pressure Education Program Working Group. Report on high blood pressure in pregnancy. Am J Obstet Gynecol 1990;163:1689. (Comprehensive consensus report.)

43. Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med 2002;347:1256. (Terse review of the relevant pathophysiology and clinical implications; 44 references.)

44. Skjaeven R, Wilcox AJ, Lie R. The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002;346:33. (Epidemiologic study; the interval between pregnancies increases risk, but change in partners does not.)

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Appendix

Appendix: Coronary Heart Disease Risk Factor Prediction Chart

Table 26.1. Coronary Heart Disease Risk Factor Prediction Chart

1. FIND POINTS FOR EACH RISK FACTOR

Women

Men

Age

Pts

Age

Pts

Age

Pts

Age

Pts

HDL-C

Pts

Total C

Pts

SBP (mm Hg)

Pts

Other

Pts

-12

47–48

-2

57–59

25–26

139–151

-3

98–104

-2

Cigarettes

-11

49–50

-1

60–61

27–29

152–166

-2

105–112

-1

Diabetic–-male

-9

51–52

32–33

62–64

30–32

167–182

-1

113–120

Diabetic–-female

-8

53–55

65–67

33–35

183–199

121–129

ECG LVH

-6

56–60

35–36

68–70

36–38

200–219

130–139

-5

61–67

37–38

71–73

39–42

220–239

140–149

0 Pts for each No

-4

68–74

43–46

240–262

150–160

-3

40–41

47–50

263–288

161–172

-2

42–43

51–55

-1

289–315

173–185

-1

44–45

56–60

-2

316–330

46–47

61–66

-3

48–49

67–73

-4

42–43

50–51

74–80

-5

52–52

81–87

-6

45–46

55–56

88–96

-7

2. SUM POINTS FOR ALL RISK FACTORS

Note: Minus points/subtract from total.

3. LOOK UP RISK CORRESPONDING TO POINT TOTAL									4. COMPARE WITH AVERAGE 10-YR RISK
Probability (%)			Probability (%)			Probability (%)			Probability (%)			Probability (%)
Pts	5 Yr	10 Yr	Pts	5 Yr	10 Yr	Pts	5 Yr	10 Yr	Pts	5 Yr	10 Yr	Age	Women	Men
≤1	<1	<2	10	2	6	19	8	16	28	19	33	30–34	<1	3
2	1	2	11	3	6	20	8	18	29	20	36	35–39	1	5
3	1	2	12	3	7	21	9	19	30	22	38	40–44	2	6
4	1	2	13	3	8	22	11	21	31	24	40	45–49	5	10
5	1	3	14	4	9	23	12	23	32	25	42	50–54	8	14
6	1	3	15	5	10	24	13	25				55–59	12	16
7	1	4	16	5	12	25	14	27				60–64	13	21
8	2	4	17	6	13	26	16	29				65–69	9	30
9	2	5	18	7	14	27	17	31				70–74	12	24
Prepared with the help of William B. Kannel, M.D., professor of medicine and public health, and Ralph D'Agostino, Ph.D., head, Department of Mathematics, both at Boston University; Keaven Anderson, Ph.D., statistician. National Heart, Lung, and Blood Institute, Framingham Study; Daniel McGee, Ph.D., associate professor, University of Arizona. Framingham Heart Study. Š1990. American Heart Association.
ECG, electrocardiogram; Pts, points; HDL, high-density lipoprotein; C, cholesterol; SBP, systolic blood pressure; LVH, left ventricular hypertension.