Overall Goal of Treatment
The overall goal of treating hypertension is to reduce morbidity and mortality from CV events (eg, coronary events, cerebrovascular events, HF) and kidney disease. Therefore, the specific selection of antihypertensive drug therapy should be based on evidence demonstrating a reduction in morbidity and mortality, not merely a reduction in BP.
Surrogate Targets—Blood Pressure Goals
Treating patients with hypertension to achieve a desired goal BP is a surrogate goal of therapy. Reducing BP to goal does not guarantee prevention of hypertension-associated complications, but is associated with a lower risk. Targeting a goal BP is how clinicians evaluate response to therapy. It is the primary method that is used to determine the need for titration and regimen modification.
The 2017 ACC/AHA guideline recommends a goal BP of <130/80 mm Hg for the management of hypertension in most patients (see “DESIRED OUTCOMES: GOAL BP FOR CHRONIC TREATMENT” box).1 The American Diabetes Association recommends a goal of <140/90 mm Hg for most patients with diabetes, with a lower goal of <130/80 mm Hg for certain individuals (eg, those at high risk of ASCVD) if achieved without undue treatment burden.15 The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend a BP goal of ≤140/90 mm Hg for patients with hypertension and CKD (nondialysis), with a lower BP goal of ≤130/80 mm Hg only for those patients who have persistent albuminuria (≥30 mg urine albumin excretion per 24 hours or equivalent) as a therapeutic option.16,17
Desired Outcomes: Goal BP for Chronic Treatment
Most patients (including patients with clinical ASCVD [secondary prevention], diabetes, or CKD; primary prevention patients regardless of 10-year ASCVD risk score):
Older ambulatory, community dwelling patients:
Institutionalized older patients, those with high disease burden and comorbidities, or limited life-expectancy:
Consider a relaxed SBP goal of at least <150 mm Hg; <140 mm Hg in some patients if tolerated
Use a team-based decision process weighing patient preferences, risks, and benefits
Historically, most patients with hypertension were treated to a goal BP of <140/90 mm Hg. However, evidence demonstrates significantly lower risk of CV events with lower BP goals, particularly in those with or at high risk of ASCVD. Some of the strongest data supporting the lower BP goals comes from the Systolic Blood Pressure Intervention Trial (SPRINT). The SPRINT evaluated a systolic BP goal of <120 mm Hg versus <140 mm Hg in patients with hypertension at high CV risk but without diabetes.18 The study was stopped early after a median follow-up of 3.3 years due to a significantly lower risk of the primary composite outcome (MI, other acute coronary syndromes, stroke, HF, or death from CV causes) and all-cause mortality in patients treated to the lower BP goals. While there was an increased risk of adverse events in the intensive treatment group (eg, hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure), the significant benefits outweighed these risks.
In addition to the SPRINT, several other systematic reviews and meta-analysis demonstrate that lower BP goals improve clinical outcomes better than higher BP goals.19–23 In a systematic review and meta-analysis of 19 trials involving 44,989 patients, intensive treatment (mean BP 133/76 mm Hg) was associated with a reduced risk of major CV events, MI, stroke, albuminuria, and retinopathy progression compared to less intensive BP-lowering (mean BP 140/81 mm Hg).20 The risk of serious adverse events with intensive therapy was low and did not differ significantly compared to less-intensive treatment, though severe hypotension was more frequent.
Evidence Supporting Lower BP Goals in Diabetes
BP goal values for patients with diabetes have been a subject of debate for a number of years. A BP goal of <130/80 mm Hg was historically recommended for patients with diabetes by multiple organizations. The primary evidence supporting this recommendation was from the Hypertension Optimal Treatment (HOT) study, which compared diastolic BP goals of <90 mm Hg, <85 mm Hg, or <80 mm Hg on CV outcomes.24 Only the subgroup of patients with diabetes (n = 1,501) had a lower risk of major CV events in the <80 mm Hg group versus the <90 mm Hg group.
However, the NHLBI-sponsored Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) study questioned the benefit of lower BP goals for patients with diabetes.25 The ACCORD-BP was an open-label, factorial study that randomized 4,733 patients with type 2 diabetes to a SBP of <120 mm Hg, or to a SBP <140 mm Hg. After a mean follow-up of 4.7 years, there was no significant difference in the annual rate of the primary endpoint (nonfatal MI, nonfatal stroke, or CV death) between the two groups. However, the annual incidence of the secondary end point of stroke was significantly lower with the <120 mm Hg goal, and this was the only prespecified end point that was different between the two groups.
Based on these data, the American Diabetes Association changed their recommendation to a goal BP of <140/90 mm Hg for most patients with hypertension and diabetes.15 However, there are important limitations to ACCORD-BP that should be considered. First, ACCORD-BP was underpowered, as only half of the expected primary composite endpoint events occurred during the study. It was also a factorial study design. A recent post-hoc analysis of ACCORD-BP that examined CV outcomes for participants with CVD risk factors that would have been eligible for the SPRINT found very similar CV event rates and adverse effect rates as seen in the SPRINT.26 Also, the evidence-based review performed for the 2017 ACC/AHA guideline found a lower risk of fatal or nonfatal stroke with lower BP goals in patients with diabetes.19 Therefore, patients with diabetes should generally be treated to a BP of <130/80 mm Hg.
Avoiding Clinical Inertia
Although hypertension is one of the most common medical conditions, BP control rates are poor. Clinical inertia in hypertension is defined as an office visit for which no therapeutic move was made to lower BP in a patient with uncontrolled hypertension.27 Clinical inertia is not the entire reason why many patients with hypertension do not achieve goal BP values. However, it is certainly a major reason that can be remedied simply through more aggressive antihypertensive drug therapy. This strategy can include initiating, titrating, or changing drug therapy.
General Approach to Treatment
All patients with elevated blood pressure, stage 1 hypertension, and stage 2 hypertension should be engaged in lifestyle modifications. For patients with elevated blood pressure and those with stage 1 hypertension who are at low risk of ASCVD (ie, primary prevention with a 10-year ASCVD risk <10%), lifestyle modification alone is an appropriate initial treatment. The threshold when drug therapy should be started for these low-risk patients is when the BP is ≥140/90 mm Hg with a goal BP of <130/80 mm Hg. For patients with stage 1 or 2 hypertension who already have ASCVD (secondary prevention) or who have an elevated 10-year ASCVD risk ≥10% (including most patients with diabetes and most patients with CKD), the threshold for starting drug therapy is ≥130/80 mm Hg with a goal BP of <130/80 mm Hg.
The choice of initial antihypertensive drug therapy depends on the degree of BP elevation and presence of compelling indications (see the section "Pharmacotherapy"). A single first-line antihypertensive drug should be started as an initial therapy in most patients with newly diagnosed hypertension presenting with stage 1 hypertension. Combination drug therapy, preferably with two first-line antihypertensive drugs, should be started as an initial therapy in patients with newly diagnosed hypertension presenting with more severe BP elevation (stage 2 hypertension). This general approach to an initial therapy is outlined in Fig. 30-2. There are several compelling indications where specific antihypertensive drug classes have evidence showing unique benefits in patients with hypertension (see Fig. 30-3). Under these circumstances, selection of antihypertensive drug therapy should follow an evidence-based order.
Algorithm for treatment of elevated BP and hypertension based on BP category at initial diagnosis. Drug therapy recommendations are graded with strength of recommendation and quality of evidence in brackets. Strength of recommendations: A, B, and C are good, moderate, and poor evidence to support recommendation, respectively. Quality of evidence: (1) evidence from more than one properly randomized controlled trial; (2) evidence from at least one well-designed clinical trial with randomization, from cohort or case-controlled studies, or dramatic results from uncontrolled experiments or subgroup analyses; (3) evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities.
Compelling indications for individual drug classes. Compelling indications for specific drugs are evidence-based recommendations from outcome studies or existing clinical guidelines. The order of drug therapies serves as a general guidance that should be balanced with clinical judgment and patient response. Add-on pharmacotherapy recommendations are when additional agents are needed to lower BP to goal values. Blood pressure control should be managed concurrently with the compelling indication. Drug therapy recommendations are graded with strength of recommendation and quality of evidence in brackets. Strength of recommendations: A, B, and C are good, moderate, and poor evidence to support recommendation, respectively. Quality of evidence: (1) evidence from more than one properly randomized controlled trial; (2) evidence from at least one well-designed clinical trial with randomization, from cohort or case-controlled analytic studies or multiple time series, or dramatic results from uncontrolled experiments or subgroup analyses; (3) evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities.
All patients with elevated blood pressure and hypertension should be prescribed lifestyle modifications. However, they should never be used as a replacement for antihypertensive drug therapy for patients with hypertension who are not at goal BP. Recommended modifications that have been shown to lower BP are listed in Table 30-4.1 Lifestyle modifications can provide small-to-moderate reductions in SBP. Aside from reducing BP in patients with known hypertension, strict adherence to lifestyle modification can decrease the progression to hypertension in patients with elevated BP values.
TABLE 30-4Lifestyle Modifications to Prevent and Manage Hypertension ||Download (.pdf) TABLE 30-4 Lifestyle Modifications to Prevent and Manage Hypertension
|Modification ||Recommendation ||Approximate SBP Reduction (mm Hg)* |
|With Hypertension ||Without Hypertension |
|Weight loss ||Maintain normal body weight (body mass index, 18.5-24.9 kg/m2), but aim for at least ≥1 kg weight reduction. Approximate 1 mm Hg BP reduction noted per 1 kg weight loss ||5 ||2-3 |
|DASH-type dietary patterns ||Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat ||11 ||3 |
|Reduced salt intake ||Reduce daily dietary sodium intake as much as possible, ideally to 1.5 g/day sodium (3.8 g/day sodium chloride) ||5-6 ||2-3 |
|Physical activity ||90-150 min/wk of aerobic or dynamic resistance training, and involving moderate to vigorous intensity† ||5-8 aerobic ||2-4 aerobic |
|4 dynamic ||2 dynamic |
|Moderation of alcohol intake ||Limit consumption to ≤2 drink equivalents per day in men and ≤1 drink equivalent per day in women and lighter-weight persons‡ ||4 ||3 |
A sensible dietary program is one that is designed to reduce weight gradually (for overweight and obese patients) and restricts sodium intake with only moderate alcohol consumption (for patients who consume alcohol). Successful implementation of dietary and lifestyle modifications by patients requires aggressive promotion by clinicians through patient education, encouragement, and continued reinforcement. Weight loss, as little as 5% of body weight, can decrease BP significantly in overweight or obese patients. Diets rich in fruits and vegetables and low in saturated fat have been shown to lower BP in patients with hypertension. Most people experience BP lowering with sodium restriction.
The Dietary Approaches to Stop Hypertension (DASH) eating plan is a diet that is rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat. It is recommended as a reasonable and feasible diet that has proven to lower BP. Intake of sodium should be minimized as much as possible, ideally to 1.5 g/day, although an interim goal of a 1 g/day reduction may be reasonable considering the challenges in achieving low sodium intake. Patients should be aware of the multiple sources of dietary sodium (eg, processed foods, soups, table salt) so that they may implement restriction. Potassium intake should be encouraged through fruits and vegetables with high content (ideally 3.5-5 g/day) in those with normal kidney function or without impaired potassium excretion. Excessive alcohol use can either cause or worsen hypertension. Patients with hypertension who drink alcoholic beverages should restrict their daily intake.
Physical activity consisting of aerobic or dynamic resistance training of 90 to 150 minutes per week (eg, 3-4 sessions per week, lasting on average 40 minutes per session) and involving moderate-to-vigorous intensity should be encouraged when possible. Studies have shown that physical activity, and in particular aerobic activity, can reduce BP, even in the absence of weight loss. Patients should consult their physicians before starting an exercise program, especially those with hypertension-associated complications.
Smoking (tobacco or other products) is not a secondary cause of essential hypertension. Therefore, smoking cessation is not a recommended strategy to control BP. However, smoking is a major, independent, modifiable risk factor for CV disease. Patients with hypertension who smoke should be counseled regarding the additional health risks that result from smoking. Moreover, the potential benefits that smoking cessation can provide should be explained to encourage cessation.
An ACEi, ARB, CCB, or a thiazide are the preferred first-line antihypertensive agents for most patients (Table 30-5).1 These agents should be used to treat the majority of patients with hypertension because of evidence demonstrating CV event reduction. Several of these medications have subclasses where significant differences in mechanism of action, clinical use, side effects, or evidence from outcome studies exist. β-Blocker therapy should be reserved to either treat a specific compelling indication or used in combination with one or more of those mentioned above first-line antihypertensive agents for patients without a compelling indication. Other antihypertensive drug classes are considered alternative drug classes that may be used in select patients after implementing first-line agents (Table 30-6).
TABLE 30-5Most Common First-Line and Other Antihypertensive Agents ||Download (.pdf) TABLE 30-5 Most Common First-Line and Other Antihypertensive Agents
|Class ||Subclass ||Medication (Brand Name) ||Usual Dose Range (mg/day) ||Daily Frequency ||Comments |
|ACEi || ||Benazepril (Lotensin) ||10-40 ||1 or 2 ||May cause hyperkalemia in patients with chronic kidney disease or in those receiving a potassium-sparing diuretic, mineralocorticoid receptor antagonist, ARB, or direct renin inhibitor; can cause acute kidney injury in patients with severe bilateral renal artery stenosis or severe stenosis in artery to solitary kidney; contraindicated in pregnancy or in patients with a history of angioedema; starting dose should be reduced 50% in patients who are on a thiazide, are volume depleted, or are very elderly due to risks of hypotension |
|Captopril (Capoten) ||12.5-150 ||2 or 3 |
|Enalapril (Vasotec) ||5-40 ||1 or 2 |
|Fosinopril (Monopril) ||10-40 ||1 |
|Lisinopril (Prinivil, Zestril) ||10-40 ||1 |
|Moexipril (Univasc) ||7.5-30 ||1 or 2 |
|Perindopril (Aceon) ||4-16 ||1 |
|Quinapril (Accupril) ||10-80 ||1 or 2 |
|Ramipril (Altace) ||2.5-10 ||1 or 2 |
|Trandolapril (Mavik) ||1-4 ||1 |
|ARB || ||Azilsartan (Edarbi) ||40-80 ||1 ||May cause hyperkalemia in patients with chronic kidney disease or in those receiving a potassium-sparing diuretic, mineralocorticoid receptor antagonist, ACEi, or direct renin inhibitor; can cause acute kidney injury in patients with severe bilateral renal artery stenosis or severe stenosis in artery to solitary kidney; do not cause a dry cough like an ACEi may; contraindicated in pregnancy; starting dose should be reduced 50% in patients who are on a thiazide, are volume depleted, or are very elderly due to risks of hypotension |
|Candesartan (Atacand) ||8-32 ||1 or 2 |
|Eprosartan (Teveten) ||600-800 ||1 or 2 |
|Irbesartan (Avapro) ||150-300 ||1 |
|Losartan (Cozaar) ||50-100 ||1 or 2 |
|Telmisartan (Micardis) ||20-40 ||1 |
|Olmesartan (Benicar) ||20-80 ||1 |
|Valsartan (Diovan) ||80-320 ||1 |
|Calcium channel blocker ||Dihydropyridine ||Amlodipine (Norvasc) ||2.5-10 ||1 ||Do not use immediate-release nifedipine or immediate-release nicardipine; dihydropyridines are more potent arterial vasodilators than nondihydropyridines and may cause more peripheral edema; may cause reflex sympathetic discharge (tachycardia); have additional benefits in Raynaud’s syndrome |
|Felodipine (Plendil) ||5-20 ||1 |
|Nifedipine long-acting (Afeditab CR Adalat CC, Nifediac CC, Nifedical XL, Procardia XL) ||30-90 ||1 |
|Nisoldipine (Sular) ||10-40 ||1 |
|Nondihydropyridine ||Diltiazem sustained release (Cardizem CD, Cartia XT, Dilacor XR, Diltia XT, Tiazac, Taztia XT) ||120-480 ||1 ||Use extended-release products for hypertension; these agents block the A-V node, reduce heart rate, and may produce heart block, especially in combination with β-blockers; not all products are not AB rated as interchangeable on an equipotent milligram-per-milligram basis due to different release mechanisms and bioavailability; Cardizem LA, Matzim LA, and Verelan PM have delayed drug release for several hours after dosing and can provide chronotherapeutic drug delivery, but this does not have any clinical advantages; have additional benefits in patients with atrial tachyarrhythmia |
|Diltiazem extended release (Cardizem LA, Matzim LA) ||180-480 ||1 (morning or evening) |
|Verapamil sustained release (Calan SR, Isoptin SR, Verelan) ||180-420 ||1 or 2 |
|Verapamil chronotherapeutic oral drug absorption system (Verelan PM) ||100-400 ||1 (in the evening) |
|Diuretic ||Thiazide ||Chlorthalidone (Thalitone) ||12.5-25 ||1 ||Hydrochlorothiazide is a “thiazide-type” while chlorthalidone, indapamide, and metolazone are “thiazide-like.” Dose in the morning to avoid nocturnal diuresis; thiazides are more effective antihypertensives than loop diuretics in most patients; use usual doses to avoid adverse metabolic effects; hydrochlorothiazide, chlorthalidone, and indapamide are preferred; chlorthalidone is approximately 1.5 times as potent as hydrochlorothiazide; have additional benefits in osteoporosis; use with caution in patients with a history of gout |
|Hydrochlorothiazide (Microzide) ||12.5-50 ||1 |
|Indapamide (Lozol) ||1.25-2.5 ||1 |
|Metolazone (Zaroxolyn) ||2.5-10 ||1 |
|Loop ||Bumetanide (Bumex) ||0.5-4 ||2 ||Dose in the morning and late afternoon (when twice daily) to avoid nocturnal diuresis; higher doses may be needed for patients with severely decreased glomerular filtration rate or HF; preferred over thiazides in patient with severe kidney dysfunction and resistant hypertension |
|Furosemide (Lasix) ||20-80 ||2 |
|Torsemide (Demadex) ||5-10 ||1 |
|Potassium sparing ||Amiloride (Midamor) ||5-10 ||1 or 2 ||Weak diuretics that are used in combination with a thiazide to minimize hypokalemia; do not significantly lower BP unless used with a thiazide; should be reserved for patients experiencing diuretic-induced hypokalemia; avoid in patients with severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2); may cause hyperkalemia, especially in combination with a mineralocorticoid receptor antagonist, ACEi, ARB, direct renin inhibitor, or potassium supplements |
|Amiloride/hydrochlorothiazide (Moduretic) ||5-50 ||1 |
|Triamterene (Dyrenium) ||50-100 ||1 or 2 |
|Triamterene/hydrochlorothiazide (Dyazide, Maxide) ||37.5-75/25-50 ||1 |
|Mineralocorticoid receptor antagonist ||Eplerenone (Inspra) ||50-100 ||1 or 2 ||Dose in the morning and late afternoon (when twice daily) to avoid nocturnal diuresis; eplerenone contraindicated in patients with an estimated creatinine clearance <50 mL/min (0.84 mL/s), elevated serum creatinine (>1.8 mg/dL [159 µmol/L] in women, >2 mg/dL [177 µmol/L] in men), or type 2 diabetes with albuminuria; often used as an add-on therapy in resistant hypertension; avoid in patients with severe chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2); may cause hyperkalemia, especially in combination with an ACEi, an ARB, direct renin inhibitor, or potassium supplements |
|Spironolactone (Aldactone, CaroSpir) ||25-50 ||1 or 2 |
|β-blocker ||Cardioselective ||Atenolol (Tenormin) ||25-100 ||1 or 2 ||Abrupt discontinuation may cause rebound hypertension; have additional benefits in patients with atrial tachyarrhythmia or preoperative hypertension; in general, cardioselective agents inhibit β1-receptors at low-to-moderate dose, higher doses may also block β2-receptors (especially metoprolol); additional vasodilation with nebivolol does not result in more orthostatic hypotension; nonselective agents inhibit β1- and β2-receptors at all doses, can exacerbate asthma, and have additional benefits in patients with essential tremor, migraine headache, portal hypertension, thyrotoxicosis. Agents with intrinsic sympathomimetic activity (acebutolol and pindolol) partially stimulate β-receptors while blocking against additional stimulation; no role in the management of hypertension and are contraindicated in patients with stable ischemic heart disease. Mixed α- and β-blockers produce vasodilation and have more orthostatic hypotension |
|Betaxolol (Kerlone) ||5-20 ||1 |
|Bisoprolol (Zebeta) ||2.5-10 ||1 |
|Metoprolol tartrate (Lopressor) ||100-200 ||2 |
|Metoprolol succinate extended release (Toprol XL) ||50-200 ||1 |
|Nebivolol (Bystolic) ||5-20 ||1 |
|Nonselective ||Nadolol (Corgard) ||40-120 ||1 |
|Propranolol (Inderal) ||160-480 ||2 |
|Propranolol long acting (Inderal LA, Inderal XL, InnoPran XL) ||80-320 ||1 |
|Timolol (Blocadren) ||10-40 ||1 |
|Mixed α- and β-blockers ||Carvedilol (Coreg) ||12.5-50 ||2 |
|Carvedilol phosphate (Coreg CR) ||20-80 ||1 |
|Labetalol (Normodyne, Trandate) ||200-800 ||2 |
TABLE 30-6Alternative Antihypertensive Agents ||Download (.pdf) TABLE 30-6 Alternative Antihypertensive Agents
|Class ||Medication (Brand Name) ||Usual Dose Range (mg/day) ||Daily Frequency ||Comments |
|α1-Blocker || || || ||Give first dose at bedtime; patients should rise from sitting or lying down slowly to minimize risk of orthostatic hypotension; additional benefits in men with benign prostatic hyperplasia |
|Direct renin inhibitor || || || ||May cause hyperkalemia in patients with chronic kidney disease and diabetes or in those receiving a potassium-sparing diuretic, mineralocorticoid receptor antagonist, ACEi, or ARB; may cause acute kidney failure in patients with severe bilateral renal artery stenosis or severe stenosis in artery to solitary kidney; do not use in pregnancy |
|Central α2-agonist || || |
| ||Abrupt discontinuation may cause rebound hypertension; most effective if used with a thiazide to diminish fluid retention; clonidine patch is replaced once per week |
|Direct arterial vasodilator || || || ||Should be used with a thiazide and β-blocker to diminish fluid retention and reflex tachycardia |
Historical Evidence Supporting Thiazide Therapy
Landmark placebo-controlled clinical trials demonstrate that thiazide therapy irrefutably reduces the risk of CV morbidity and mortality. The Systolic Hypertension in the Elderly Program (SHEP),9 Swedish Trial in Old Patients with Hypertension (STOP-Hypertension),8 and Medical Research Council (MRC) studies showed significant reductions in stroke, MI, all-cause CV disease, and mortality with thiazide-based therapy versus placebo. These trials used β-blockers as an add-on therapy for BP control. Agents such as an ACEi, an ARB, and a CCB were not available at the time of these studies. However, subsequent clinical trials have compared these antihypertensive agents with a thiazide and have demonstrated similar long-term benefits.28–34
The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
The results of the ALLHAT were the deciding evidence that the JNC7 used to justify thiazide therapy as a first-line therapy.28 It was designed to test the hypothesis that newer antihypertensive agents (an α-blocker, an ACEi, or a dihydropyridine CCB) would be superior to thiazide-based therapy. The primary objective was to compare the combined end point of fatal CHD and nonfatal MI. Other hypertension-related complications (eg, HF, stroke) were evaluated as secondary end points. This was the largest prospective hypertension trial ever conducted and included 42,418 patients aged 55 and older with hypertension and one additional CV risk factor. This double-blind trial randomized patients to chlorthalidone-, amlodipine-, doxazosin-, or lisinopril-based therapy for a mean of 4.9 years.
The doxazosin treatment arm was terminated early when a significantly higher risk of HF versus chlorthalidone was observed.35 The other arms were continued as scheduled and no significant differences in the primary endpoint were seen between the chlorthalidone and lisinopril or amlodipine treatment groups at the end of the trial. However, chlorthalidone had statistically fewer secondary endpoints than amlodipine (HF) and lisinopril (combined CV disease, HF, and stroke). The study conclusions were that chlorthalidone-based therapy was superior in preventing one or more major forms of CV disease and was less expensive than amlodipine- or lisinopril-based therapy.
The ALLHAT was designed as a superiority study with the hypothesis that amlodipine, doxazosin, and lisinopril would be better than chlorthalidone.36 It did not prove this hypothesis. Several subgroup analyses of specific populations (eg, black patients, CKD, diabetes) from the ALLHAT have been conducted to assess response in certain unique patient populations.37–39 Surprisingly, none of these analyses demonstrated superior CV event reductions with lisinopril or amlodipine versus chlorthalidone. Overall, thiazides remain unsurpassed in their ability to reduce CV morbidity and mortality in most patients.
Like the JNC7 guideline, the 2017 ACC/AHA high BP guideline recommends a thiazide as a first-line therapy for most patients.1 However, an ACEi, an ARB, and a CCB are also comparable first-line options. Contrary to the historical preference to use a thiazide as preferred for treating most patients with hypertension, they are simply one of four first-line drug therapy options. Figure 30-2 displays the algorithm for the treatment of hypertension and highlights four first-line antihypertensive options for patients without a compelling indication for a specific drug class.
ACEi, ARB, and CCB as First-Line Agents
Clinical trial data cumulatively demonstrate that ACEi-, CCB-, and ARB-based antihypertensive therapy reduce CV events. These agents are first-line options for patients without a compelling indication. The Blood Pressure Lowering Treatment Trialists’ Collaboration has evaluated the incidence of major CV events and death among different antihypertensive drug classes from 29 major randomized trials in 162,341 patients.40 In placebo-controlled trials, major CV events were significantly lower with ACEi- and CCB-based regimens versus placebo. Although there were minor differences in the incidence of certain CV events in some comparisons, there were no differences in total major CV events when an ACEi, a CCB, or a thiazide was compared with each other. In studies evaluating ARB-based therapy to control regimens, the incidence of major CV events was lower with ARB-based therapy. However, the control regimens used in these comparisons included both antihypertensive drug therapies and placebo. These results were largely consistent with the network meta-analysis conducted for the 2017 ACC/AHA guideline, which found that an ACEi, an ARB, a CCB, and a thiazide were all similar as first-line treatment for hypertension.19
Data from meta-analyses that incorporate high-quality randomized controlled trials provide more robust data than any single trial alone. High-quality meta-analyses provide clinically useful data that support using ACEi-, CCB-, or ARB-based treatment for hypertension as first-line antihypertensive agent. Clinicians should use meta-analyses data as supporting evidence when selecting a first-line antihypertensive regimen for hypertension in most patients.
Other major consensus guidelines recommend several first-line drug therapy options for treating hypertension in most patients. The 2013 European Society of Hypertension/European Society of Cardiology guidelines and the 2011 UK’s National Institute for Health and the Clinical Excellence guidelines recommend an ACEi, an ARB, a CCB, or a thiazide as first-line treatment.41,42 The European Society of Hypertension/European Society of Cardiology guidelines are founded on the principle that CV risk reduction is a function of BP control that is largely independent of specific antihypertensives.41 The UK guideline stratifies patients based on age and race; they recommend an ACEi or ARB first-line for patients under the age of 55 years, and a CCB first-line for patients age 55 years or older or for black patients.42
β-Blocker Versus First-Line Agents
Clinical trial data and meta-analyses cumulatively suggest that treatment with a β-blocker may not reduce CV events to the extent that an ACEi, an ARB, a CCB, or particularly a thiazide does.1 In the systematic review and network analysis conducted for the 2017 ACC/AHA guideline, β-blockers were less effective for the prevention of stroke and CV events than diuretics.19
Meta-analyses data evaluating β-blockers and their ability to reduce CV events have limitations. Most studies that were included in these analyses used atenolol as the β-blocker studied. Therefore, it is possible that atenolol is inferior and is the only β-blocker that does not reduce CV events as much as other first-line antihypertensive drug classes. A recent network meta-analysis comparing the effects of different β-blockers found a decreased risk of mortality and CV events with lipophilic agents (metoprolol, propranolol, and oxprenolol) compared to hydrophilic agents (atenolol).43 However, due to challenges in the interpretation of meta-analyses of β-blockers compared to other first-line agents (eg, trials conducted at different times, use of different beta-blockers, changes in the efficacy of agents, etc.), most guideline recommendations do not differentiate between the β-blocker drug class.41,42 In the absence of a compelling indication, the 2011 UK guideline recommends a β-blocker as a fourth-line therapy, only after other first-line antihypertensive agents (ACEi or ARB, CCB, thiazide) have been used.42 These findings also call into question the validity of results from prominent prospective, controlled clinical trials evaluating antihypertensive drug therapy that used β-blocker–based therapy, especially atenolol, as the primary comparator.30,32 These studies used once-daily atenolol, which in addition to being hydrophilic, may have been inadequately dosed based on the short half-life of this agent.
β-Blocker–based antihypertensive therapy does not increase the risk of CV events; β-blocker–based therapy reduces the risk of CV events compared with no antihypertensive therapy. Using a β-blocker as a first-line antihypertensive agent is an option when an ACEi, an ARB, a CCB, or a thiazide cannot be used. β-Blockers also have an important role as an add-on therapy to first-line agents to reduce BP in patients with hypertension but without compelling indications.
Many of the clinical trials included in the meta-analyses that suggest β-blocker–based therapy may not reduce CV events as well as these other agents, used atenolol dosed once daily.44 Atenolol has a half-life of 6 to 7 hours and is nearly always dosed once daily, while immediate-release forms of carvedilol and metoprolol have half-lives of 6 to 10 and 3 to 7 hours, respectively, and are dosed at least twice daily.44 It is also, hydrophilic, which may not penetrate the brain and cell membrane as easily as lipophilic agents, and has been shown to be inferior to lipophilic agents (metoprolol, propranolol, and oxprenolol).43 Therefore, it is possible that these findings might only apply to atenolol, particularly dosed once daily instead of twice daily. Based on available evidence, metoprolol succinate or carvedilol are the preferred β-blockers if a β-blocker is to be used.
Patients with Compelling Indications
Compelling indications represent specific comorbid conditions where evidence from clinical trials supports using specific antihypertensive classes to treat both the compelling indication and hypertension. Antihypertensive medication recommendations typically consist of combination drug therapy (see Fig. 30-3). Data from clinical trials have demonstrated a reduction in CV morbidity and/or mortality that justify use for patients with hypertension and with such a compelling indication.
Heart Failure with Reduced Ejection Fraction
Five drug classes have compelling indications for HF with reduced ejection fraction (HFrEF), also known as systolic HF or left ventricular dysfunction.45 The primary physiologic abnormality in HFrEF is decreased CO resulting from a decreased left ventricular ejection fraction. An evidence-based pharmacotherapy regimen for HFrEF, called guideline-directed medical therapy, consists of three to four drugs: an ACEi or ARB plus diuretic therapy, followed by the addition of an evidence-based β-blocker (ie, bisoprolol, carvedilol, metoprolol succinate) and possibly a mineralocorticoid receptor antagonist.
Evidence from clinical trials shows that ACEi therapy significantly modifies disease progression by reducing morbidity and mortality. Although HFrEF was the primary disease in these studies, ACEi therapy will also control BP in these patients with concomitant hypertension. An ARB is an acceptable alternative for patients who cannot tolerate an ACEi. An ACEi or ARB should be started using a low dose in HFrEF, especially in patients with an acute exacerbation of HF. Acute HF exacerbation induces a compensatory high-renin condition, so starting an ACEi or ARB under these conditions can cause a pronounced first-dose effect and possible orthostatic hypotension.
Diuretics are a component of standard pharmacotherapy, primarily to provide symptomatic relief of edema by inducing diuresis. Loop diuretics are often needed, especially for patients with more advanced HF and/or CKD. However, some patients with well-controlled HF and without significant CKD may be managed with a thiazide.
β-Blocker therapy modifies disease in HFrEF and is a component of standard treatment for these patients. For patients on an initial regimen of a diuretic with an ACEi or ARB, add-on β-blocker therapy has been shown to reduce CV morbidity and mortality.46 It is of paramount importance that β-blockers be dosed appropriately due to the risk of inducing an acute exacerbation of HF. They must be started in very low doses (much lower than that used to treat hypertension), and titrated slowly to high doses based on tolerability. Bisoprolol, carvedilol, and metoprolol succinate are the only β-blockers that are proved to be beneficial in HFrEF.
After implementation of a standard three-drug regimen (diuretic, ACEi or ARB, and evidence-based β-blocker), other agents may be added to further reduce CV morbidity and mortality, and reduce BP if needed. The addition of a mineralocorticoid receptor antagonist (e.g. spironolactone) can reduce CV morbidity and mortality in HFrEF.46 For patients self-described as African Americans, addition of a fixed-dose combination of isosorbide dinitrate and hydralazine to the standard three-drug regimen (diuretic, ACEi or ARB, and evidence-based β-blocker) is a recommended option to improve CV outcomes.45
Heart Failure with Preserved Ejection Fraction
Approximately 50% of patient with HF have a preserved ejection fraction (HFpEF). In HFpEF, patients have signs and symptoms of HF such as dyspnea, fatigue, and possibly edema, but they have a preserved left ventricular ejection fraction (≥50%).
Unlike interventions using GDMT in HFrEF that have been shown to decrease morbidity and mortality in HF, trials using the same medications in HFpEF have not shown similar benefits.46 Therefore, treatment should be targeted at any underline symptoms, appropriate management of any underlying coronary artery disease, and attainment of goal BP to prevent progression of HF. Patients should use a β-blocker or an ACEi or ARB for treatment of hypertension, but if signs and symptoms of edema are present, they should receive a diuretic.1
Stable Ischemic Heart Disease
Chronic stable angina and a history of acute coronary syndrome (unstable angina or acute MI) are forms of stable ischemic heart disease (aka, coronary artery disease).1 These are the most common forms of hypertension-associated complications. Patients with ischemic heart disease are at high risk for a CVD event.
β-Blocker therapy has been a standard of care for treating patients with stable (and unstable) ischemic heart disease and hypertension for decades. β-Blockers are first-line therapy in stable ischemic heart disease and can reduce BP and improve angina symptoms by decreasing myocardial oxygen consumption and demand.1 They also decrease cardiac adrenergic stimulation and have been shown in clinical trials to reduce the risk of a subsequent MI and sudden cardiac death. β-Blocker therapy seems to be most effective in reducing the risk of CV events in patients with recent MI and/or ischemic symptoms. While data are available that indicates that the long-term risk of CV events and mortality may not be reduced with β-blocker therapy in patients with very stable coronary artery disease (ie, do not have ischemic symptoms or have a distant history of MI),47 β-blockers should be used for treatment of hypertension in patients with stable ischemic heart disease.1 An ACEi (or an ARB as an alternative) has been shown to improve cardiac remodeling and cardiac function and to reduce CV events in stable ischemic heart disease as an add-on to a β-blocker.
A long-acting nondihydropyridine CCB is an alternative to a β-blocker (diltiazem and verapamil) in stable ischemic heart disease.48 The International Verapamil–Trandolapril Study (INVEST) demonstrated no difference in CV risk reduction when β-blocker–based therapy was compared with nondihydropyridine CCB-based treatment in this population.49 Nonetheless, the preponderance of data is with β-blockers, and they remain the therapy of choice.1,48
A dihydropyridine CCB (eg, amlodipine, felodipine) is recommended as an add-on therapy in stable ischemic heart disease patients who have ongoing ischemic symptoms (aka, angina or chest pain).48 CCBs (especially nondihydropyridine CCBs) and β-blockers provide anti-ischemic effects; they lower BP and reduce myocardial oxygen demand in patients with hypertension and stable (and unstable) ischemic heart disease. However, cardiac stimulation may occur with dihydropyridine CCBs (particularly immediate release formulations) or β-blockers with intrinsic sympathomimetic activity (ISA), making these agents less desirable. Moreover, β-blockers with ISA should be avoided due to these deleterious effects.
Once ischemic symptoms are controlled with β-blocker and/or CCB therapy, other antihypertensive drugs can be added to provide additional CV risk reduction. Clinical trials have demonstrated that the addition of an ACEi further reduces CV events in patients with stable ischemic heart disease.48 ARB therapy may provide similar benefits but have not been as extensively studied as ACEi therapy. Therefore, in stable ischemic heart disease, an ARB is generally considered an alternative to an ACEi. Thiazides can be added after that to provide additional BP lowering and to reduce CV risk further. However, thiazides do not provide anti-ischemic effects.
The primary cause of mortality in patients with diabetes is CV disease, and hypertension management is an important risk reduction strategy.1 All four first-line antihypertensive agents (ACEi, ARB, CCB, thiazides) have been shown to reduce CV events in patients with diabetes (see Fig. 30-3).1 The evidence-based review performed for the 2017 ACC/AHA guideline found no difference in all-cause mortality, CV mortality, HF, or stroke between ACEi-, ARB-, CCB-, and thiazide-based regimens in patients with diabetes.19
Traditionally, an ACEi or ARB was considered as a preferred antihypertensive agent for patients with diabetes.2 The reasons for this were that pharmacologically both of these agents should provide nephroprotection due to vasodilation in the efferent arteriole of the kidney. Moreover, ACEi therapy has strong data demonstrating CV risk reduction in patients with established forms of heart disease. Evidence from clinical studies have demonstrated reductions in both CV risk (mostly with an ACEi) and reduction in risk of progressive kidney dysfunction (mostly with ARBs) in patients with diabetes.15,50 However, data indicate that an ACEi or ARB does not confer significantly better CV risk reduction compared to CCBs, thiazides, or β-blockers in patients with diabetes.51 In addition, the risk of kidney disease progression is low in absence of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g [3.4 mg/mmol creatinine]),15 and many of the studies evaluating the ability of an ACEi or ARB to slow progression of kidney dysfunction were placebo controlled.51 Therefore, an ACEi or ARB is recommended similarly to a CCB or thiazide in patients with diabetes and hypertension that do not have persistent albuminuria.15
After first-line antihypertensives (ACEi, ARB, CCB, thiazide), a β-blocker is a useful add-on therapy for BP control for patients with diabetes, or to treat another compelling indication (eg, stable ischemic heart disease). A β-blocker (especially nonselective agents) can possibly mask the signs and symptoms of hypoglycemia in patients with tightly controlled diabetes because most of the symptoms of hypoglycemia (eg, tremor, tachycardia, and palpitations) are mediated through the sympathetic nervous system. Sweating, a cholinergically mediated symptom of hypoglycemia, still occurs during a hypoglycemic episode despite β-blocker therapy. Patients may also have a delay in hypoglycemia recovery time because compensatory recovery mechanisms need the catecholamine inputs that are antagonized by β-blocker therapy. Finally, unopposed α-receptor stimulation during the acute hypoglycemic recovery phase (due to endogenous epinephrine release intended to reverse hypoglycemia) may result in acutely elevated BP due to vasoconstriction. Despite these potential problems, β-blockers can be safely used for patients with diabetes.
Based on the weight of all evidence, any first-line agent can be used for controlling hypertension for patients with diabetes in the absence of albuminuria. Regardless of what agent is initially chosen, most patient will require combination therapy, which typically will include an ACEi or ARB with a CCB or thiazide.
Hypertension can damage the renal tissue (parenchyma) and/or the renal arteries.16 CKD in patients with hypertension initially presents as moderately increased albuminuria (urine albumin-to-creatinine ratio 30 to 299 mg/g [3.4 to 34 mg/mmol creatinine] on a spot urine sample or ≥30 mg albumin in a 24-hour urine collection) that can progress to overt kidney failure. The rate of kidney function deterioration is accelerated when both hypertension and diabetes are present. Patients with significant CKD (eg, GFR <60 mL/min/1.73 m2 and/or albuminuria) have increased risk of CV disease and further progression to severe CKD.1 BP control can slow the decline in kidney function and reduce the risk of a CV event in patients with CKD.
In addition to lowering BP, ACEi and ARB therapies can reduce intraglomerular pressure, which can theoretically provide additional benefits by further reducing the decline in kidney function. ACEi or ARB therapy has been shown to slow progression of CKD in patients with diabetes17,50 and those without diabetes.52 It is difficult to differentiate whether the kidney protection benefits are from RAAS blockade versus BP lowering. A meta-analysis failed to demonstrate any unique long-term kidney protective effects of RAAS-blocking drugs compared with other antihypertensive drugs, suggesting that benefits may be attributed to BP lowering.53 Moreover, a subgroup analysis of patients from the ALLHAT stratified by different baseline GFR values also did not show a difference in long-term outcomes with chlorthalidone versus lisinopril among patients with significant CKD.37
Patients may experience a rapid and profound drop in BP or acute kidney injury when initially starting an ACEi or ARB. The potential to produce acute kidney injury is particularly problematic in patients with significant bilateral renal artery stenosis or a solitary functioning kidney with stenosis. Patients with renal artery stenosis are usually older, and this condition is more common in patients with diabetes or those who smoke. Patients with renal artery stenosis do not always have evidence of kidney disease unless specific tests are performed. Starting with low dosages and evaluating serum creatinine soon after starting either an ACEi or ARB can minimize this risk.
Secondary Stroke Prevention
Ischemic stroke (not hemorrhagic stroke) and transient ischemic attack (TIA) are considered hypertension-associated complications. More than two-thirds of patients who have had an ischemic stroke or TIA have hypertension.1 Achieving goal BP values in patients who have experienced an ischemic stroke is considered a primary modality to reduce the risk of a second stroke or TIA. A thiazide, either in combination with an ACEi or as monotherapy, is an evidence-based antihypertensive regimen for patients with a history of stroke or transient ischemic attack.1,54,55 ARB-based therapy has also been studied in this population.56,57 Antihypertensive drug therapy should only be implemented after patients have stabilized following an acute cerebrovascular event, typically a few days after the event.1 Moreover, the threshold for starting antihypertensive drug therapy in patients with a history of stroke is when BP is above 140/90 mm Hg.1 Once antihypertensive therapy is initiated, these patients should be treated to a goal of <130/80 mm Hg.
Alternative Drug Treatments
It is sometimes necessary to use other agents such as a direct renin inhibitor, an α-blocker, a central α2-agonist, an adrenergic inhibitor, or an arterial vasodilator in some patients. Although these agents are effective in lowering BP, they either do not have convincing evidence showing reduced morbidity and mortality in hypertension or have a high incidence of adverse effects that significantly hinders tolerability. Alternative agents are generally reserved for patients with resistant hypertension or as an add-on therapy with multiple other first-line antihypertensive agents.
Selection of drug therapy should follow the recommendations provided by evidence-based guidelines, which are summarized in Figs. 30-2 and 30-3.1 These should be maintained as the guiding principles of drug therapy. However, there are some patient populations where the approach to drug therapy may be slightly altered or utilize recommended agents using tailored dosing strategies. In some cases, this is because other agents have unique properties that benefit a coexisting condition, but may not be based on evidence from outcome studies in hypertension.
Hypertension in Older People
Hypertension often presents as isolated systolic hypertension in older patients.1 Epidemiologic data indicate that CV morbidity and mortality are more directly correlated to SBP than to DBP for patients aged 50 and older. This population is also at high risk for hypertension-associated complications.1 Although several placebo-controlled trials have specifically demonstrated risk reduction in this population, many older people with hypertension are either not treated or treated but not to goal BP.
The SHEP was a landmark double-blind, placebo-controlled trial that evaluated chlorthalidone-based treatment for isolated systolic hypertension.9 A 36% reduction in total stroke, a 27% reduction in coronary artery disease, and 55% reduction in HF were demonstrated versus placebo. The Systolic Hypertension in Europe (Syst-Eur) trial was another placebo-controlled trial that evaluated treatment with a long-acting dihydropyridine CCB.10 Treatment resulted in a 42% reduction in stroke, 26% reduction in coronary artery disease, and 29% reduction in HF. These data demonstrate reductions in CV morbidity and mortality in older patients with isolated systolic hypertension, especially with thiazides and long-acting dihydropyridine CCBs.
The “very elderly” population (80 years of age and older) were underrepresented in the SHEP and Syst-Eur studies. Historically, this population often was not treated to goal either because of a fear of side effects or because of limited evidence demonstrating benefit. However, the Hypertension in the Very Elderly Trial (HYVET) provided definitive evidence that antihypertensive drug therapy provides significant clinical benefits in these patients.58 The HYVET was a prospective controlled clinical trial that randomized patients 80 years and older with hypertension to placebo or antihypertensive drug therapy. It was stopped early after a median of only 1.8 years because the incidence of death was 21% higher in placebo-treated patients. Based on these results, hypertension should be treated in patients age 80 years and older.
Thiazide or β-blocker therapy has been compared with either an ACEi or CCB in older patients with either systolic hypertension, diastolic hypertension, or both in the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) study.59 In this trial, no significant differences in the primary CV event endpoint were seen between conventional drugs and either an ACEi or CCB. These data support that overall treatment may be more important than specific antihypertensive agents in this population.
Older patients are more sensitive to volume depletion and sympathetic inhibition than younger patients. This may lead to orthostatic hypotension (see the next section). In older patients, this can increase the risk of falls due to the associated dizziness. Centrally acting agents and α1-blockers should generally be avoided or used with caution in older patients because they are frequently associated with dizziness and orthostatic hypotension. First-line antihypertensives provide significant benefits and can safely be used in older patients, especially those age 80 years and older, but smaller-than-usual initial doses must be used for initial therapy.
The most appropriate BP goal for older patients has been a matter of significant debate. In 2003 the JNC7 recommended the same general BP goal of <140/90 mm Hg regardless of age.2 However, in 2014 the panel members appointed to the Eighth Joint National Committee (JNC 8) recommended a less strict BP goal of <150/90 mm Hg in patients older than 60 years.60 This recommendation sparked substantial disagreement and debate, with panel members appointed to the JNC8 who disagreed with this recommendation publishing a “minority view” citing concerns with the impact on public health and interpretation of the evidence.61
The best evidence for lower BP goals in older patients comes from the SPRINT-Senior trial, which was a prespecified subanalysis of patients 75 years and older who were enrolled in the SPRINT study.62 In this cohort, older (mean age 79.9 years), community-dwelling patients without dementia and an expected life expectancy of 3 or more years who were treated to a SBP of <120 mm Hg compared a SBP of <140 mm Hg experienced a 34% reduced risk of the primary composite outcome of CVD and 33% reduced risk of all-cause mortality. While the lower SBP goal was associated with an increased risk of hypotension and electrolyte abnormalities, there was no difference in serious adverse events. The benefits of lower BP goals in older patients significantly outweighed the risk, though careful monitoring is essential to ensure safe medication use. A recent meta-analysis examining the risks and benefits of lower BP compared to a “relaxed” goal of <150 mm Hg found similar results.63 Therefore, based on the totality of evidence, older, ambulatory patients should be treated to a SBP goal of <130 mm Hg.1
The treatment of hypertension in older patients should follow the same principles that are outlined for general care of hypertension. However, in patients with multiple comorbidities or disease states, or in whom the benefit of therapy may be less established (eg, nursing home resident, dementia, etc.), the risks and benefits of using a lower BP goal should be considered, taking into account patient preference and using a team-based approach. In these patients, a relaxed SBP goal of at least <150 mm Hg (<140 mm Hg in some patients if tolerated) should be considered appropriate. Also, while the general approach to treatment is similar compared to younger patients, initial drug doses may be lower, and dosage titrations over a longer period are usually needed to minimize the risk of hypotension.
Patients at Risk for Orthostatic Hypotension
Orthostatic hypotension is a significant drop in BP when standing and can be associated with dizziness and/or fainting. It is defined as a SBP decrease of >20 mm Hg or DBP decrease of >10 mm Hg when changing from supine to standing.1 The risk of orthostatic hypotension is increased in older patients (especially those with isolated systolic hypotension, or those age 80 years or older) and those with long-standing diabetes, severe volume depletion, baroreflex dysfunction, autonomic insufficiency (eg, diabetes), and concomitant use of medications that cause venodilation (α-blockers, mixed α-/β-blockers, nitrates, and phosphodiesterase inhibitors). For patients with these risk factors, antihypertensive agents, especially a thiazide, an ACEi, or an ARB should be started in low doses.
Hypertension in Children and Adolescents
Detecting hypertension in children requires customized evaluation. Hypertension is defined as SBP or DBP that is >95th percentile for sex, age, and height on at least three occasions for children.64 BP values between the 90th and 95th percentile, or >120/80 mm Hg in adolescents, is considered elevated BP. Hypertensive children often have a family history of high BP, and many are overweight or obese, predisposing them to insulin resistance and associated CV risk. Unlike hypertension in adults, secondary hypertension is more common in children and adolescents. An appropriate workup for secondary causes is required if elevated BP is identified. Kidney disease (eg, pyelonephritis, glomerulonephritis) is the most common cause of secondary hypertension in children.
Nonpharmacologic treatment (eg, weight loss if overweight or obese, healthy diet, sleep, physical activity) is the cornerstone of therapy for essential hypertension in children.64 The goal is to reduce the BP to <90th percentile for sex, age, and height and <130/80 mm Hg in adolescents age 13 years and older.64 An ACEi, an ARB, a β-blocker, a CCB, and a thiazide are all acceptable choices in children and have data supporting their use.64 If an ACEi or ARB is to be used in adolescents girls of childbearing age, it is important to counsel regarding the risk of fetal injury and death since these agents are teratogenic and an alternative antihypertensive may be considered. As with adults, selection of initial agents should be based on the presence of compelling indications or concurrent conditions that may warrant their use.
Hypertension during pregnancy is a major cause of maternal and neonatal morbidity and mortality.1 Hypertension during pregnancy is categorized as preeclampsia-eclampsia, chronic hypertension (of any cause), chronic hypertension superimposed preeclampsia, and gestational hypertension.65 Preeclampsia is defined as hypertension (elevated BP ≥140/90 mm Hg on more than two occasions at least 4 hours apart after 20 weeks’ gestation or ≥160/110 mm Hg confirmed within a short interval) in association with thrombocytopenia, impaired liver function, new-onset renal insufficiency, pulmonary edema, or new-onset cerebral or visual disturbances. It can lead to life-threatening complications for both mother and fetus. Eclampsia, the onset of convulsions in preeclampsia, is a medical emergency. Chronic hypertension is hypertension that predates pregnancy; superimposed preeclampsia is chronic hypertension associated with preeclampsia. Gestational hypertension is defined as new-onset hypertension arising after 20 weeks of gestation in the absence of proteinuria or other systemic findings (eg, thrombocytopenia, renal insufficiency, pulmonary edema, cerebral or visual disturbances).
It is controversial whether treating mild-to-moderate hypertension in pregnancy is beneficial. However, women with chronic hypertension prior to pregnancy are at increased risk of a number of complications including superimposed preeclampsia, preterm delivery, fetal growth restriction or demise, placental abruption, HF, and acute kidney failure.65 In an open, international, multicenter study of nonproteinuric preexisting or gestational hypertension, tighter DBP goals (<85 mm Hg) were not associated with decreased rates of the primary composite outcome of pregnancy loss or high-level neonatal care compared to less-tight control (DBP <100 mm Hg).66 However, severe hypertension (≥160/110 mm Hg) developed less often in patients randomized to the tight control group compared to less-tight control (40.6% vs 27.5%).
Definitive treatment of preeclampsia is delivery. Labor induction is indicated if pending or frank eclampsia is present. Otherwise, management consists of restricting activity, bed rest, and close monitoring. Salt restriction, or any other measures that contract blood volume, should not be employed. Antihypertensive agents are used before induction of labor if DBP is greater than 105 mm Hg with a target DBP of 95 to 105 mm Hg. Intravenous (IV) hydralazine is most commonly used, and IV labetalol is also effective. Immediate-release oral nifedipine has been used in the past but is not approved by the FDA for hypertension, and untoward fetal and maternal effects (hypotension with fetal distress) have been reported.
Many agents can be used to treat chronic hypertension in pregnancy (Table 30-7). Unfortunately, there are few data regarding the most appropriate therapy in pregnancy. Labetalol, long-acting nifedipine, or methyldopa is recommended as a first-line agent due to favorable safety profile.65 Other β-blockers (not atenolol) and CCBs are also reasonable alternatives. An ACEi, an ARB, and a direct renin inhibitor are known teratogens and are absolutely contraindicated.
TABLE 30-7Treatment of Chronic Hypertension in Pregnancy ||Download (.pdf) TABLE 30-7 Treatment of Chronic Hypertension in Pregnancy
|Medication/Class ||Comments |
|Methyldopa ||Long-term follow-up data support safety; considered a preferred agent |
|β-blockers ||Generally safe, but intrauterine growth retardation reported (mostly with atenolol) |
|Labetalol ||Increasingly used over methyldopa because of fewer side effects; considered a first-line agent |
|Clonidine ||Limited data available; mainly an option in the third trimester |
|CCB ||Limited data available; no increase in major teratogenicity with exposure (except immediate-release oral nifedipine should not be used); long-acting nifedipine considered a preferred agent |
|Thiazide ||Not first-line agents but probably safe in low doses if started prior to conception when treating essential hypertension |
|ACEi, ARB, direct renin inhibitor ||Contraindicated; major teratogenicity reported with exposure (fetal toxicity and death) |
Hypertension affects African American patients at a disproportionately higher rate, and hypertension-associated complications are more prevalent than in other populations.1 Reasons for these differences are not fully understood but may be related to differences in underlying physiologic alterations. Hypertension is also more difficult to control in African Americans and usually requires two or more antihypertensives to reach a goal of <130/80 mm Hg.1
BP-lowering effects of antihypertensive medication classes vary in African Americans. However, these differences are only relevant when monotherapy treatment is utilized. CCBs and thiazides are most effective at lowering BP in African Americans and should be used first-line in the absence of a compelling indication.1 When either of these two classes (especially thiazides) are used in combination with a β-blocker, an ACEi, or an ARB (which are three classes known to be less effective at lowering BP in African Americans), the antihypertensive response is significantly increased. This may be due to the low-renin pattern of hypertension in African Americans, which can result in less BP lowering with a β-blocker, an ACEi, or an ARB when used as monotherapy compared with white patients. Interestingly, African Americans have a higher risk of angioedema from an ACEi compared with whites.1
Despite potential differences in antihypertensive effects with monotherapy treatment, drug therapy selection should be based on evidence, no different from what is recommended for the hypertensive population in general. Medications recommended for specific compelling indications should be used when such compelling indications are present, even if the antihypertensive effect may not be as great as with another drug class (eg, use a β-blocker first-line for hypertension in an African American with stable ischemic heart disease or an ACE or ARB in an African American with CKD).
Most patients with hypertension have some other coexisting conditions that may influence selection of drug therapy. The influence of comorbid conditions should only be complementary to, and never in replacement of, drug therapy choices recommended to treat a compelling indication. Under some circumstances, these considerations are helpful in deciding on a particular antihypertensive agent when more than one antihypertensive class is recommended. In some cases, an agent should be avoided because it may aggravate a concomitant disorder. In other cases, an antihypertensive can be used to treat hypertension, and another concomitant condition. These are briefly summarized in Table 30-5.
Pulmonary Disease and Peripheral Arterial Disease
β-Blockers, especially nonselective agents, have generally been avoided for patients with hypertension and reactive airway disease (asthma or chronic obstructive pulmonary disease [COPD] with a reversible obstructive component) due to a fear of inducing bronchospasm. However, cardioselective β-blockers can safely be used in patients with asthma or COPD.1 Therefore, cardioselective β-blockers should be used to treat a compelling indication (ie, stable ischemic heart disease, or HF) for patients with reactive airway disease.
PAD is a noncoronary form of ASCVD. Patients with PAD are at an increased risk of stroke and CV events.1,67 While β-blockers can theoretically be problematic for patients with PAD due to possible decreased peripheral blood flow secondary to unopposed stimulation of α1-receptors that results in vasoconstriction, available data indicate that β-blockers do not worsen claudication symptoms or cause functional impairment.67 Antihypertensive treatment for patients with PAD should follow the same general principles as patients without PAD.1
Metabolic syndrome is a cluster of multiple cardiometabolic risk factors.1 It has been defined as the presence of three of the following five criteria: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated BP (or receiving drug treatment for high BP), and elevated fasting blood glucose.68 Despite the debate regarding whether the metabolic syndrome is a true “disease” or simply a cluster of conditions, it is widely accepted that patients with metabolic syndrome are at increased risk of developing CV disease and/or type 2 diabetes. The cornerstone of treatment involves lifestyle modification (eg, weight loss if overweight or obese, exercise, dietary modifications). There are no definitive evidence that any first-line antihypertensive medication class is better or worse than another in reducing CV events in patients with metabolic syndrome.1 While thiazides have been associated with a small increase in blood glucose and faster progression to diabetes, a subgroup analysis of the ALLHAT found that CV events were reduced more with chlorthalidone when compared to lisinopril in patients with impaired fasting glucose.38 Therefore, any first-line antihypertensive can be used for patients with metabolic syndrome.
Most antihypertensive agents, particularly β-blockers, and mineralocorticoid receptor antagonists, have been associated with erectile dysfunction in men. However, it is not clear if erectile dysfunction associated with antihypertensive treatment is solely a result of drug therapy or rather a symptom of underlying vascular disease. β-Blockers have historically been labeled as agents that cause significant sexual dysfunction. However, evidence supporting this notion are limited. A systematic review of 15 studies involving 35,000 patients assessing β-blocker use for MI, HF, and hypertension found only a very slight increased risk for erectile dysfunction.69 In addition, prospective long-term data from the Treatment of Mild Hypertension Study (TOMHS) and the Veterans Administration cooperative trial show no difference in the incidence of erectile dysfunction between a thiazide and β-blocker versus an ACEi and CCB.70,71 Centrally acting agents are associated with higher rates of sexual dysfunction and should be avoided in men with erectile dysfunction.
Hypertensive men frequently have ASCVD, which frequently results in erectile dysfunction. Therefore, erectile dysfunction is associated with chronic arterial changes resulting from elevated BP, and lack of control may increase the risk of erectile dysfunction. These changes are even more pronounced in hypertensive men with diabetes.
Resistant hypertension is defined as failure to achieve goal BP with the use of three or more antihypertensive drugs with complementary mechanisms of action (ideally using optimal doses, one of which is a diuretic) or when four or more antihypertensive drugs are needed to achieve BP control.1,72 Using the previous BP goal of <140/90 mm Hg, it has been estimated that 12% of patients with hypertension fall under this definition.4 With the new BP goal of <130/80 mm Hg, an additional 4% of patients (18% total) may meet criteria for resistant hypertension.1 Patients with newly diagnosed hypertension or who are not receiving drug therapy should not be considered to have resistant hypertension. Difficult-to-control hypertension is persistently elevated BP despite treatment with two or three drugs, which fails to meet the criteria for resistant hypertension.
Several causes of resistant hypertension are listed in Table 30-8. Volume overload is a common cause, thus highlighting the importance of diuretic therapy in the management of hypertension. Pseudoresistance should also be ruled out by assuring adherence with prescribed therapy and possibly use of out-of-office BP measurements (by using a self-monitoring device or 24-hour ABP monitor).1 Patients should be closely evaluated to see if any of these causes can be reversed.
TABLE 30-8Causes of Resistant Hypertension
Treatment of patients with resistant hypertension should ultimately follow the principles of drug therapy selection from the 2017 ACC/AHA guideline. Compelling indications, if present, should guide selection assuming these patients are on a thiazide or other type of diuretic. However, there are treatment philosophies that are germane to the management of resistant hypertension: (a) assuring adequate diuretic therapy, (b) appropriate use of combination therapy, and (c) using alternative antihypertensive agents when needed.
Assuring Appropriate Diuretic Therapy
Diuretics have a large role in the pharmacotherapy of resistant hypertension. Thiazides are first-line antihypertensive agents, but chlorthalidone (thiazide-like) should be preferentially used ahead of hydrochlorothiazide, especially for patients with resistant hypertension, because it is more potent on a milligram-per-milligram basis.1,73 Clinicians should identify that chlorthalidone, like all thiazides, has dose-dependent metabolic side effects (hypokalemia and hyperglycemia) and that appropriate monitoring should be implemented. However, it does not seem as though side effects are more common with chlorthalidone versus hydrochlorothiazide. Though less commonly used, indapamide (similar to chlorthalidone as “thiazide like”) is also a more potent antihypertensive agent than hydrochlorothiazide at commonly prescribed doses, and evidence does not demonstrate a higher risk of metabolic side effects.74
A mineralocorticoid receptor antagonist (eg, spironolactone) is also highly effective as an add-on agent.1 Data indicate that many patients with resistant hypertension have some degree of underlying hyperaldosteronism, justifying the role of adding a mineralocorticoid receptor antagonist. Spironolactone has been compared to an α-blocker and a β-blocker as an add-on therapy for resistant hypertension in the PATHWAY-2 study.75 The BP-lowering effect of spironolactone was approximately double that of doxazosin and bisoprolol, reinforcing the benefits of blocking aldosterone by using a mineralocorticoid receptor antagonist in managing resistant hypertension.
Clinicians may consider using a loop diuretic, even in place of a thiazide, for patients with resistant hypertension who have very compromised kidney function (estimated GFR <30 mL/min/1.73 m2).1 Torsemide can be dosed once daily while furosemide must be dosed twice daily or three times daily.
First-Line Antihypertensive Agents
Angiotensin-Converting Enzyme Inhibitors (ACEi)
An ACEi is a first-line therapy option in most patients with hypertension.1 The ALLHAT demonstrated less HF and stroke with chlorthalidone versus lisinopril,28 while another outcome study demonstrated similar, if not better, outcomes with an ACEi versus hydrochlorothiazide.34 It is possible that the different thiazides have different abilities to reduce CV events. Nonetheless, strong evidence demonstrates that ACEi therapy overall reduces CV events comparably to other first-line antihypertensive agents.
ACE facilitates production of angiotensin II that has a major role in arterial BP regulation as depicted in Fig. 30-1. ACE is distributed in many tissues and is present in several different cell types, but its principal location is in endothelial cells. Therefore, the major site for angiotensin II production is in the blood vessels, not the kidney. An ACEi blocks the ACE, thus inhibiting the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor that stimulates aldosterone secretion, causing an increase in sodium and water reabsorption with accompanying potassium loss. By blocking the ACE, vasodilation and a decrease in aldosterone occur.
An ACEi also blocks degradation of bradykinin and stimulates the synthesis of other vasodilating substances (prostaglandin E2 and prostacyclin). Because an ACEi lowers BP in patients with normal plasma renin activity, bradykinin and perhaps tissue production of ACE are important in hypertension. Increased bradykinin enhances the BP-lowering effects of an ACEi, but also is responsible for the side effect of a dry cough. An ACEi may effectively prevent or regress LVH by reducing direct stimulation of angiotensin II on myocardial cells.
There are many evidence-based indications for an ACEi (see Fig. 30-3). An ACEi reduces CV morbidity and mortality in patients with HFrEF and decreases progression of CKD. They are first-line as disease-modifying therapy in all of these patients unless contraindicated. An ACEi is a first-line option for patients with diabetes and hypertension because of demonstrated CV disease and kidney benefits. A regimen including an ACEi with a thiazide is first-line in recurrent stroke prevention based on benefits demonstrated from the PROGRESS trial showing a reduced risk of secondary stroke.33 As an add-on to β-blocker therapy, evidence indicates that an ACEi further reduces CV risk in patients with stable ischemic heart disease, especially in patients post-MI.76–78 These benefits of an ACEi occur in patients with ASCVD even in the absence of LV dysfunction and may reduce the development of new-onset type 2 diabetes.79
Most ACEi medications can be dosed once daily for hypertension (Table 30-5). In some patients, especially when higher doses are used, twice-daily dosing is needed to maintain 24-hour effects with enalapril, benazepril, moexipril, quinapril, and ramipril.
ACEi therapy is generally well tolerated. Because they decrease aldosterone, an increase in potassium serum concentrations can occur. While this increase is usually small, hyperkalemia is possible. Patients with CKD or those taking potassium supplements, potassium-sparing diuretics, mineralocorticoid receptor antagonists, ARBs, or a direct renin inhibitor are at highest risk for hyperkalemia. Judicious monitoring of serum potassium and creatinine values within 4 weeks of starting or increasing the dose of an ACEi can often identify abnormalities early before they evolve into serious adverse events.
The most worrisome adverse effect of ACEi therapy is acute kidney injury. This serious adverse effect is uncommon, and the development of severe acute kidney failure is very rare, occurring in less than 1% of patients. Preexisting kidney disease increases the risk of this side effect. Severe bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on the efferent arteriole of the kidney, thus explaining why these patients are particularly susceptible to acute kidney injury from an ACEi. Slow titration of the ACEi dose and judicious kidney function monitoring can minimize risk and allow for early detection of patients with renal artery stenosis.
It is important to note that GFR does decrease somewhat in patients when started on an ACEi.1 This is attributed to the inhibition of angiotensin II vasoconstriction on the efferent arteriole. This decrease in GFR often increases serum creatinine, and small increases should be anticipated when monitoring patients newly started on an ACEi. Either modest elevations of ≤35% (for baseline creatinine values ≤3 mg/dL [265 μmol/L]) or absolute increases <1 mg/dL (88 μmol/L) do not warrant changes. If larger increases occur, ACEi therapy should be stopped or the dose reduced.
Angioedema is a serious potential complication of ACEi therapy. It occurs in <1% of the population, and is more likely in African Americans and smokers. Symptoms include lip and tongue swelling and possibly difficulty breathing. Drug withdrawal is appropriate for treating patients with angioedema. However, angioedema associated with laryngeal edema and/or pulmonary symptoms occasionally occurs and requires additional treatment with a bradykinin B2 receptor antagonist (eg, icatibant), fresh frozen plasma, and/or emergent intubations to support respiration. A history of angioedema, even if not from an ACEi, precludes the use of another ACEi (it is a contraindication). Cross-reactivity between an ACEi and an ARB does not appear to be a significant concern. The Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial enrolled 75 patients with a history of ACEi–induced angioedema, and randomized these patients to either placebo or ARB therapy.80 There were no cases of repeat angioedema among these patients. These data suggest the cross-reactivity is very low. Hence, an ARB can be used in a patient with a history of ACEi–induced angioedema when it is needed. However, clinicians should monitor for repeat occurrences, since idiopathic angioedema may still occur.
A persistent dry cough may develop in up to 20% of patients treated with an ACEi. It is pharmacologically explained by the inhibition of bradykinin breakdown. This cough does not cause pulmonary disease but is annoying and can compromise adherence. It should be differentiated from a wet cough due to pulmonary edema, which may be a sign of uncontrolled HF and not ACEi–induced cough.
An ACEi (as well as an ARB or direct renin inhibitor) is absolutely contraindicated in pregnancy. Female patients of childbearing age should be counseled regarding effective forms of birth control as ACEi therapy is fetotoxic.1 Fetopathy (group of conditions that include renal failure, renal dysplasia, hypotension, oligohydramnios, pulmonary hypotension, hypocalvaria, and death) has occurred with ACEi exposure in the second and third trimesters. Similar to a thiazide, an ACEi can increase lithium serum concentrations in patients on lithium therapy. Concurrent use of an ACEi with a potassium-sparing diuretic, potassium supplements, mineralocorticoid receptor antagonist, ARB, or direct renin inhibitor may result in hyperkalemia.
Starting doses of an ACEi should be low, with even lower doses for patients at risk for orthostatic hypotension or severe renal dysfunction (eg, elderly patients, those with CKD). Acute hypotension may occur at the onset of ACEi therapy. Patients who are sodium or volume depleted, in an HF exacerbation, very elderly, or on concurrent vasodilators or thiazide therapy, are at high risk for this effect. It is important to start with half the normal dose of an ACEi for all patients with these risk factors and to use slow dose titration.
Angiotensin Receptor Blockers (ARBs)
Angiotensin II is generated by two enzymatic pathways: the RAAS, which involves ACE, and an alternative pathway that uses other enzymes such as chymase (aka “tissue ACE”). An ACEi inhibits only the effects of angiotensin II produced through the RAAS, whereas ARBs inhibit the effects of angiotensin II from all pathways. It is unclear how these differences affect tissue concentrations of ACE.
ARB therapy directly blocks the AT1 receptor that mediates the known effects of angiotensin II in humans: vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction of the efferent arterioles of the glomerulus. They do not block the AT2 receptor. Therefore, beneficial effects of AT2 receptor stimulation (vasodilation, tissue repair, and inhibition of cell growth) remain intact with ARB use. Unlike an ACEi, an ARB does not block the breakdown of bradykinin. Therefore, some of the beneficial effects of bradykinin (eg, vasodilation, regression of myocyte hypertrophy and fibrosis, increased levels of tissue plasminogen activator) are not present with ARB therapy.
An ARB is a first-line therapy option in most patients with hypertension.1 ARB therapy has been directly compared with ACEi therapy in patients with high CV risk.81 The Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial (ON-TARGET) was a double-blind trial that randomized 25,620 patients (69% with a history of hypertension-based historical standards, mean BP of 142/82 mm Hg) to ACEi–based therapy, ARB-based therapy, or the combination of an ACEi with an ARB. The primary endpoint was a composite endpoint of CV death or hospitalization for HF. After a median follow-up of 56 months, there was no difference in the primary endpoint between any of the three treatment groups. Therefore, these data establish that the CV event–lowering benefits of ARB therapy is similar to ACEi therapy. Moreover, the combination of an ACEi with an ARB had no additional CV event lowering but was associated with a higher risk of side effects (renal dysfunction, hypotension). Therefore, there is no reason to use an ACEi with an ARB for the management of hypertension.
For patients with type 2 diabetes and CKD, the progression of kidney disease has been shown to be significantly reduced with ARB therapy.50 Some benefits appear to be independent of BP lowering, suggesting that the pharmacologic effects of ARBs on the efferent arteriole may result in attenuated progression of kidney disease. For patients with HFrEF, ARB therapy has been shown to reduce the risk of hospitalization for HF when used as an alternative therapy in ACEi-intolerant patients.46
ARBs have been compared head-to-head with CCBs. The Morbidity and Mortality After Stroke: Eprosartan Versus Nitrendipine in Secondary Prevention (MOSES) trial demonstrated that eprosartan reduced the risk of recurrent stroke greater than nitrendipine in patients with a past medical history of cerebrovascular disease.56 These data support the common notion that ARBs may have cerebroprotective effects that may explain CV event reductions. Another outcome study, the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, showed that valsartan-based therapy is equivalent to amlodipine-based therapy for the primary composite outcome of first CV event in patients with hypertension and additional CV risk factors.32 However, the occurrence of certain components of the primary endpoint (stroke and MI) and new-onset type 2 diabetes was lower in the valsartan group. Although patients treated with amlodipine had slightly lower mean BP values than valsartan-treated patients, there was no difference in the primary endpoint.
The addition of a CCB or thiazide to an ARB significantly increases antihypertensive efficacy. Similar to an ACEi, most ARBs have long enough half-lives to allow for once-daily dosing. However, candesartan, eprosartan, losartan, and valsartan have the shortest half-lives and may require twice-daily dosing for sustained BP lowering.
ARB therapy has the lowest incidence of side effects compared with other antihypertensive agents.82 ARBs do not affect bradykinin and do not elicit a dry cough like an ACEi. While referred to as an “ACEi without a cough,” pharmacologic differences between an ARB and ACEi highlight that they could have very different effects on vascular smooth muscle and myocardial tissue that can correlate to different effects. Regardless, they are first-line options for hypertension, and they are reasonable alternatives for patients that fail to tolerate ACEi therapy because of a cough. Due to their excellent tolerability, safety profile, and generic availability, ARBs are increasingly preferred by clinicians over an ACEi for hypertension.
An ARB may cause renal insufficiency, hyperkalemia, and orthostatic hypotension in a manner identical to that of an ACEi. The same precautions that apply to ACEi therapy regarding suspected bilateral renal artery stenosis, concomitant medications that can raise potassium, and/or increase in the risk of hypotension also apply to ARBs. As previously discussed, patients with a history of ACEi angioedema can be treated with an ARB when needed.83 An ARB should never be used in pregnancy.
Calcium Channel Blockers (CCBs)
Both dihydropyridine CCBs and nondihydropyridine CCBs are first-line therapies for hypertension.1 CCBs also have compelling indications in stable ischemic heart disease. However, with this compelling indication, they are primarily used as an add-on therapy to other antihypertensive drug classes.
Contraction of cardiac and smooth muscle cells requires an increase in free intracellular calcium concentrations from the extracellular fluid. When cardiac or vascular smooth muscle is stimulated, voltage-sensitive channels in the cell membrane are opened, allowing calcium to enter the cells. The influx of extracellular calcium into the cell releases stored calcium from the sarcoplasmic reticulum. As intracellular free calcium concentration increases, it binds to a protein, calmodulin, which then activates myosin kinase enabling myosin to interact with actin to induce contraction. CCBs work by inhibiting the influx of calcium across the cell membrane. There are two types of voltage-gated calcium channels: a high-voltage channel (L-type) and a low-voltage channel (T-type). Currently available CCBs only block the L-type channel, which leads to coronary and peripheral vasodilation.
The two subclasses, dihydropyridines and nondihydropyridines (see Table 30-5), are pharmacologically very different from each other. Antihypertensive effectiveness is similar with both, but they differ somewhat in other pharmacodynamic effects. Nondihydropyridines (verapamil and diltiazem) decrease heart rate and slow atrioventricular nodal conduction. Similar to a β-blocker, these drugs may also treat supraventricular tachyarrhythmias (eg, atrial fibrillation). Verapamil (and diltiazem to a lesser extent) produces negative inotropic and chronotropic effects that are responsible for its propensity to precipitate or cause systolic HF in high-risk patients. All CCBs (except amlodipine and felodipine) have negative inotropic effects. Dihydropyridines may cause a baroreceptor-mediated reflex tachycardia because of their potent peripheral vasodilating effects. This effect appears to be more pronounced with the first-generation dihydropyridines (eg, nifedipine) and is significantly diminished with the newer agents (eg, amlodipine) and when given in sustained-release dosage forms. Dihydropyridines do not alter conduction through the atrioventricular node and thus are not effective agents in supraventricular tachyarrhythmias.
Dihydropyridine CCBs have been extensively studied in hypertension. In the ALLHAT there was no difference in the primary outcome between chlorthalidone and amlodipine, and only the secondary outcome of HF was higher with amlodipine.28 A subgroup analysis of the ALLHAT directly compared amlodipine with lisinopril and demonstrated that there was no difference in the primary outcome.84 However, amlodipine was superior to lisinopril for BP control in black patients, and for stroke reduction in black patients and women. There was a lower risk of HF in the lisinopril group. As discussed previously, the VALUE study also showed no difference between valsartan and amlodipine in the primary outcome of first CV event in high-risk patients.32
Dihydropyridine CCBs are very effective in older patients with isolated systolic hypertension. The placebo-controlled Syst-Eur trial demonstrated that a long-acting dihydropyridine CCB reduced the risk of CV events markedly in isolated systolic hypertension.10 A long-acting dihydropyridine CCB, similar to a thiazide, should be strongly considered as preferred therapy in a patient with isolated systolic hypertension and no other compelling indications.
Among dihydropyridine CCBs, short-acting nifedipine may rarely cause an increase in the frequency, intensity, and duration of angina in association with acute hypotension. This effect is most likely due to reflex sympathetic stimulation and is likely obviated by using sustained-release formulations of nifedipine. For this reason, all other dihydropyridines have an intrinsically long half-life or are sustained-release formulations. Immediate-release nifedipine has been associated with an increased incidence of adverse CV effects, is not approved for treatment of hypertension, and should never be used to treat hypertension. Other side effects of dihydropyridine CCBs include dizziness, flushing, headache, gingival hyperplasia, peripheral edema, mood changes, and various GI complaints. Side effects due to vasodilation such as dizziness, flushing, headache, and peripheral edema occur more frequently with all dihydropyridine CCBs than with the nondihydropyridine CCBs because they are less potent vasodilators.
Diltiazem and verapamil are nondihydropyridine CCBs that can cause cardiac conduction abnormalities such as bradycardia or atrioventricular block. These problems occur mostly with high doses or when used for patients with preexisting cardiac conduction abnormalities. HF has been reported in otherwise healthy patients due to negative inotropic effects. Both drugs can cause peripheral edema and hypotension. Verapamil causes constipation in about 7% of patients. This side effect also occurs with diltiazem, but to a lesser extent.
Verapamil and diltiazem are considered moderate cytochrome P450 3A4 isoenzyme system inhibitors and can cause drug interactions. These medications can increase serum concentrations of other drugs that are metabolized by this isoenzyme system (eg, cyclosporine, digoxin, lovastatin, simvastatin, tacrolimus, theophylline). Verapamil and diltiazem should be given very cautiously with a β-blocker because there is an increased risk of heart block with these combinations. When a CCB is needed in combination with a β-blocker for BP lowering, a dihydropyridine should be selected because it will not increase the risk of heart block. The hepatic metabolism of CCBs, especially felodipine, nicardipine, nifedipine, and nisoldipine, may be inhibited by ingesting large quantities of grapefruit juice (eg, ≥1 quart [or 1 L] daily).
Many different formulations of verapamil and diltiazem are currently available (see Table 30-5). Although certain individual sustained-release verapamil and diltiazem products contain the same active drug, they are usually not AB-rated by the FDA as interchangeable on a milligram-per-milligram basis due to different biopharmaceutical release mechanisms. However, the clinical significance of these differences is likely negligible.
Two nondihydropyridine CCBs, sustained-release verapamil (Verelan PM) and long-acting diltiazem (Cardizem LA), are designed to target the circadian BP rhythm. When dosed in the evening, drug is released during the early morning hours when BP first starts to increase. Targeting medication release at specific times of day is termed chronotherapy. The rationale behind chronotherapy in hypertension is that blunting the early morning BP surge may result in greater reductions in CV events than dosing of conventional antihypertensive products in the morning. However, evidence from the Controlled Onset Verapamil Investigation of Cardiovascular End-Points (CONVINCE) trial showed that chronotherapeutic verapamil was similar to, but not better than, a thiazide–β-blocker–based regimen with respect to CV events.29 Therefore, there is no specific advantage for the use of chronotherapeutic CCBs in treating hypertension.
Thiazides and other Diuretics
There are four subclasses of diuretics: thiazides, loops, potassium-sparing agents, and mineralocorticoid receptor antagonists (see Table 30-5).73 A thiazide is the preferred diuretic for hypertension and is considered a first-line therapy option in most patients.1 The best available evidence justifying this recommendation is from the ALLHAT.28 Moreover, when combination therapy is needed in hypertension to control BP, a thiazide as an add-on agent, but not necessarily the second agent, is very effective in augmenting BP lowering.
Loop diuretics are more potent agents for inducing diuresis, but are not ideal antihypertensive agents unless treating edema is also needed. In general, loop diuretics are sometimes required over a thiazide for hypertension in patients with severe CKD when estimated GFR is <30 mL/min/1.73 m2, especially when edema is present.73 However, many patients with an estimated GFR of <30 mL/min/1.73 m2, but not on dialysis, will still have antihypertensive effects with thiazides. This is especially true with chlorthalidone.73
Potassium-sparing diuretics are very weak antihypertensive agents when used alone and provide minimal additive effect when used in combination with a thiazide or loop diuretic. Their use in hypertension is in combination with another diuretic to counteract the potassium-wasting properties of the other diuretic agent.
Mineralocorticoid receptor antagonists (spironolactone and eplerenone) inhibit aldosterone activity and are sometimes considered potassium-sparing diuretics. However, they are more potent as antihypertensives and should be viewed as an independent class due to evidence supporting different compelling indications. Mineralocorticoid receptor antagonists are most commonly used to treat resistant hypertension, as elevated aldosterone concentrations are prevalent in this setting. They are also used as an add-on agent in patients with HFrEF with or without concomitant hypertension.
The exact antihypertensive mechanism of action of diuretics is not known but has been well hypothesized. The drop in BP seen when diuretics are first started is caused by an initial diuresis. Diuresis causes reductions in plasma and stroke volume, which decreases CO and BP. This initial drop in CO causes a compensatory increase in PVR. With chronic diuretic therapy, extracellular fluid and plasma volume return to near pretreatment values. However, PVR decreases to values that are lower than the pretreatment baseline. This reduction in PVR is responsible for persistent antihypertensive effects.
With thiazides, additional actions may further explain their antihypertensive effects. They mobilize sodium and water from arteriolar walls. This effect would lessen the amount of physical encroachment on the lumen of the vessel created by the excessive accumulation of intracellular fluid. As the diameter of the lumen relaxes and increases, there is less resistance to the flow of blood and PVR further drops. High dietary sodium intake can blunt this effect and a low salt intake can enhance this effect. Thiazides are also postulated to cause direct relaxation of vascular smooth muscle.
Diuretics should be dosed in the morning when given once daily and in the morning and late afternoon when dosed twice daily to minimize nocturnal diuresis. However, with chronic use, thiazides, potassium-sparing diuretics, and mineralocorticoid receptor antagonists rarely cause a pronounced diuresis.
The major pharmacokinetic differences between the different thiazide medications are serum half-life and duration of diuretic effect. The clinical relevance of these differences is unknown because the serum half-life of most antihypertensive agents does not correlate with the hypotensive duration of action. Moreover, diuretics lower BP primarily through extrarenal mechanisms. Hydrochlorothiazide and, to a greater extent, chlorthalidone are the two most frequently used thiazides in landmark clinical trials that have demonstrated reduced morbidity and mortality. Hydrochlorothiazide is considered a “thiazide-type” agent while chlorthalidone is a “thiazide-like” agent. These agents are not equipotent on a milligram-per-milligram basis; chlorthalidone is 1.5 to 2 times more potent than hydrochlorothiazide.73 This is likely attributed to a longer half-life (45-60 hours vs 8-15 hours) and longer duration of effect (48-72 hours vs 16-24 hours) with chlorthalidone.
Thiazides are effective in lowering BP, especially when used in combination with most other antihypertensives. This additive response is explained by two independent pharmacodynamic effects. First, when two drugs cause the same overall pharmacologic effect (BP lowering) through different mechanisms of action, their combination usually results in an additive or synergistic effect. This is especially relevant when a β-blocker, an ACEi, or an ARB is indicated in an African American but does not elicit sufficient antihypertensive effect. Adding a thiazide, similar to a CCB, in this situation can often significantly lower BP. Second, a compensatory increase in sodium and fluid retention may be seen with antihypertensive agents. This problem is counteracted with the concurrent use of a thiazide.
Side effects of a thiazide include hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia, and sexual dysfunction. Many of these side effects were identified when high doses of thiazides were used in the past (eg, hydrochlorothiazide up to 200 mg/day). Current guidelines recommend dosing hydrochlorothiazide up to 50 mg/day or chlorthalidone up to 25 mg/day, which markedly reduces the risk for most metabolic side effects. However, these doses, which are most effective for BP lowering, increases the risk of hypokalemia.85 Loop diuretics may cause the same side effects. Although the effect on serum lipids and glucose is even less significant, hypokalemia is more pronounced, and hypocalcemia may occur.
Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps. However, serious cardiac arrhythmias can occur in patients with severe hypokalemia and hypomagnesemia. Low-dose therapy (ie, 25 mg hydrochlorothiazide or 12.5 mg chlorthalidone daily) causes less electrolyte disturbances than higher doses. However, because the most effective doses of these two thiazides are hydrochlorothiazide 50 mg daily and chlorthalidone 25 mg daily, efforts should be made to keep potassium in the therapeutic range by careful monitoring, especially when higher doses are used.
Thiazide-induced hyperuricemia can precipitate gout. This side effect may be especially problematic for patients with a previous history of gout and is more common with thiazides. However, acute gout is unlikely in patients with no previous history of gout. If gout does occur in a patient who requires thiazide therapy, allopurinol can be given to prevent gout and will not compromise the antihypertensive effects of the thiazide. High doses of thiazide and loop diuretics may increase fasting glucose and serum cholesterol values. These effects, however, usually are transient and often inconsequential.73
Potassium-sparing diuretics can cause hyperkalemia, especially in patients with CKD or diabetes and in patients receiving concurrent treatment with a mineralocorticoid receptor antagonist, ACEi, ARB, direct renin inhibitor, or potassium supplements. Hyperkalemia is especially problematic for the mineralocorticoid receptor antagonist eplerenone, which is a very selective antagonist of aldosterone. Due to this increased risk of hyperkalemia, eplerenone is contraindicated for patients with impaired kidney function or type 2 diabetes with proteinuria (see Table 30-5). While spironolactone may cause gynecomastia in up to 10% of patients, this rarely occurs with eplerenone.
A thiazide can be used safely with most other agents. However, concurrent administration with lithium may result in increased lithium serum concentrations and can predispose patients to lithium toxicity.
β-Blockers have been used in several large outcome trials in hypertension. However, in most of these trials, a thiazide was the first-line agent with a β-blocker added for additional BP lowering. For patients with hypertension but without compelling indications, a β-blocker should not be used as the initial first-line agent. This recommendation is based on meta-analyses that suggest β-blocker–based therapy may not reduce CV events as well as these other agents when used as the initial drug to treat patients with hypertension who do not have a compelling indication for a β-blocker.1
A β-blocker is only an appropriate first-line agent in hypertension when used to treat specific compelling indications (eg, ischemic heart disease, HFrEF). Numerous trials have shown a reduced risk of CV events when β-blockers are used following an MI, during an acute coronary syndrome, or in patients with chronic stable angina with ischemic symptoms. Although once contraindicated in HF, studies have shown that bisoprolol, carvedilol, and metoprolol succinate reduce mortality in patients with HFrEF who are treated with a diuretic and ACEi.
Several mechanisms of action have been proposed for β-blockers, but none alone has been shown to be consistently associated with a reduction in arterial BP. β-Blocker therapy has negative chronotropic and inotropic effects that reduce CO, which explains some of the antihypertensive effects. However, CO falls equally for patients treated with a β-blocker regardless of BP lowering. Additionally, β-blockers with ISA do not reduce CO, yet they lower BP and decrease peripheral resistance.
β-Adrenoceptors are also located on the surface membranes of juxtaglomerular cells, and a β-blocker inhibits these receptors and thus the release of renin. However, there is a weak association between plasma renin and antihypertensive efficacy of β-blocker therapy. Some patients with low plasma renin concentrations do respond to β-blocker therapy. Therefore, additional mechanisms likely also account for the antihypertensive effect of a β-blocker.
There are important pharmacodynamic and pharmacokinetic differences among β-blockers, but all agents provide a similar degree of BP lowering. There are three pharmacodynamic properties of β-blocker therapy that differentiate this class: cardioselectivity, ISA, and membrane-stabilizing effects. β-Blocker agents that possess a greater affinity for β1-receptors than for β2-receptors are cardioselective.
β1-Adrenoceptors and β2-adrenoceptors are distributed throughout the body, but they concentrate differently in certain organs and tissues. There is a preponderance of β1-receptors in the heart and kidney, and a preponderance of β2-receptors in the lungs, liver, pancreas, and arteriolar smooth muscle. β1-Receptor stimulation increases heart rate, contractility, and renin release. β2-Receptor stimulation results in bronchodilation and vasodilation. A cardioselective β-blocker is not likely to provoke bronchospasm and vasoconstriction. Insulin secretion and glycogenolysis are mediated by β2-receptors. Blocking β2-receptors may reduce these processes and increase blood glucose or blunt recovery from hypoglycemia.
Cardioselective β-blockers (eg, bisoprolol, metoprolol, nebivolol) have clinically significant advantages over nonselective agents (eg, propranolol, nadolol), and are preferred when using a β-blocker to treat hypertension. Cardioselective agents are safer than nonselective agents for patients with asthma or diabetes who have a compelling indication for a β-blocker. However, cardioselectivity is a dose-dependent phenomenon; at higher doses, some cardioselective agents lose their relative selectivity for β1-receptors and block β2-receptors as effectively as they block β1-receptors. The dose at which cardioselectivity is lost varies from patient to patient and may not occur with highly selective β-blockers (eg, bisoprolol).
Some β-blockers (eg, acebutolol, pindolol) have ISA and act as partial β-receptor agonists. When they bind to the β-receptor, they stimulate it, but far less than a pure β-agonist. If the sympathetic tone is low, as it is during resting states, β-receptors are partially stimulated by ISA β-blockers. Therefore, resting heart rate, CO, and peripheral blood flow are not reduced when these types of β-blockers are used. Theoretically, ISA agents appear to have advantages over a non-ISA β-blockers in certain patients with HF or sinus bradycardia. Unfortunately, they do not appear to reduce CV events as well as other β-blockers. In fact, they may increase CV risk in patients with stable ischemic heart disease. Thus, agents with ISA are rarely needed and have no role in the management of hypertension.
All β-blockers exert a membrane-stabilizing action on cardiac cells when large doses are given. This activity is needed when β-blockers are used as an antiarrhythmic agent, but not for hypertension.
Pharmacokinetic differences among β-blockers relate to first-pass metabolism, route of elimination, the degree of lipophilicity, and serum half-lives. Propranolol and metoprolol undergo extensive first-pass metabolism, so the dose needed to attain β-blockade with either drug varies from patient to patient. Atenolol and nadolol are renally excreted. The dose of these agents may need to be reduced for patients with moderate-to-severe CKD.
β-Blockers, especially those with high lipophilic properties, penetrate the central nervous system and may cause other effects. Propranolol is the most lipophilic, and atenolol is the least lipophilic. Therefore, higher brain concentrations of propranolol compared with atenolol are seen after equivalent doses are given. It is thought that higher lipophilicity is associated with more central nervous system side effects (dizziness, drowsiness). However, the lipophilic properties provide better effects for non-CV conditions such as migraine headache prevention, essential tremor, and thyrotoxicosis. BP lowering is equal among β-blockers regardless of lipophilicity.
Most side effects of β-blockers are extensions of their ability to antagonize β-adrenoceptors. β-Blockade in the myocardium can be associated with bradycardia, atrioventricular conduction abnormalities (eg second- or third-degree heart block), and the development of acute HF. The decrease in heart rate may benefit certain patients with atrial arrhythmias (atrial fibrillation, atrial flutter) and hypertension by both providing rate control and BP lowering. β-Blocker therapy usually only produces HF if used in high initial doses for patients with preexisting left ventricular dysfunction or if started in these patients during an acute HF exacerbation. Blocking β2-receptors in arteriolar smooth muscle may cause cold extremities and may aggravate intermittent claudication or Raynaud’s phenomenon as a result of decreased peripheral blood flow. Also, there is an increase of sympathetic tone during periods of hypoglycemia in patients with diabetes that may result in a significant increase in BP because of unopposed α-receptor-mediated vasoconstriction.
Abrupt cessation of β-blocker therapy can produce cardiac ischemia (aka, angina or chest pain), a CV event, or even death in patients with coronary artery disease. Abrupt cessation may also lead to rebound hypertension (a sudden increase in BP to or above pretreatment values). To avoid this, β-blockers should always be tapered gradually over 1 to 2 weeks before eventually discontinuing the drug. This acute withdrawal syndrome is believed to be secondary to progression of underlying coronary disease, hypersensitivity of β-adrenergic receptors due to upregulation, and increased physical activity after withdrawal of a drug that decreases myocardial oxygen requirements. For patients without coronary disease, abrupt discontinuation may present as tachycardia, sweating, and generalized malaise in addition to increased BP.
Like a thiazide, β-blocker therapy has been shown to increase serum cholesterol and glucose values, but these effects are transient and of little-to-no clinical significance. For patients with diabetes, the reduction in CV events was as great with β-blocker therapy as with an ACEi in the United Kingdom Prospective Diabetes Study (UKPDS)86 and far superior to placebo in the SHEP trial.9 In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, patients with diabetes and hypertension who were randomized to metoprolol tartrate had an increase in hemoglobin A1C values, while patients randomized to carvedilol did not.87 This suggests that mixed α- and β-blocking effects of carvedilol may be preferential to metoprolol for patients with uncontrolled diabetes. However, differences in hemoglobin A1C values were small.
Nebivolol is a third-generation β-blocker. Similar to carvedilol and labetalol, this β-blocker results in vasodilation. However, carvedilol and labetalol cause vasodilation because of their ability to block α1-receptors, while nebivolol causes vasodilation through the release of nitric oxide. There are no proven long-term clinical benefits of the nitric oxide effects seen with nebivolol, but this might explain a lower risk of β-blocker–associated fatigue, erectile dysfunction, and metabolic side effects (eg, hyperglycemia) with this agent.
Alternative antihypertensive agents may be used as an add-on therapy to provide additional BP lowering in patients who are already treated with combination therapy consisting of first-line antihypertensives.
Selective α1-receptor blockers (doxazosin, prazosin, and doxazosin) work in the peripheral vasculature and inhibit the uptake of catecholamines in smooth muscle cells resulting in vasodilation and BP lowering.
Doxazosin was one of the original treatment arms of the ALLHAT. However, it was stopped prematurely when more secondary endpoints of stroke, HF, and CV events were seen with doxazosin compared with chlorthalidone.35 There were no differences in the primary endpoint of fatal coronary heart disease and nonfatal MI. These data demonstrated that thiazides are superior to α1-blockers in preventing CV events in patients with hypertension. Therefore, α1-blockers should only be used in combination with first-line antihypertensive agents.
An α1-blocker can provide symptomatic benefits in men with benign prostatic hypertrophy. These agents block postsynaptic α1-adrenergic receptors located on the prostate capsule, causing relaxation and decreased resistance to urinary outflow. However, when used to lower BP, they should only be in addition to first-line antihypertensive agents.
A potentially severe side effect of an α1-blocker is a “first-dose” phenomenon that is characterized by transient dizziness or faintness, palpitations, and even syncope within 1 to 3 hours of the first dose. This adverse reaction can also happen after dose increases. These episodes are accompanied by orthostatic hypotension and can be mitigated by taking the first dose and subsequent first increased doses at bedtime. Because orthostatic hypotension and dizziness may persist with chronic administration, these agents should be used very cautiously in older patients that are at an increased risk of falls. Even though antihypertensive effects are achieved through a peripheral α1-receptor antagonism, these agents cross the blood–brain barrier and may cause central nervous system side effects such as lassitude, vivid dreams, and depression. α1-Blocker therapy also may cause priapism. Sodium and water retention can occur with higher doses, and sometimes even with chronic administration of low doses. Therefore, these agents are most effective when given in combination with a thiazide to maintain antihypertensive efficacy and minimize potential edema.
Aliskiren is the only direct renin inhibitor. This drug blocks the RAAS at its point of activation, which results in reduced plasma renin activity and BP lowering.
The role of this drug class in the management of hypertension is very limited. Aliskiren is approved as monotherapy or in combination therapy. Since aliskiren is a RAAS blocker, it should not be used in combination with an ACEi or ARB because of a higher risk of serious adverse effects without providing additional reduction in CV events.1
Many of the cautions and adverse effects observed with an ACEi or ARB applies to aliskiren. Aliskiren should never be used in pregnancy due to the known teratogenic effects of using other drugs that block the RAAS system. Angioedema has also been reported in patients treated with aliskiren, as have increases in serum creatinine and serum potassium values. The mechanisms of these adverse effects are likely similar to those with an ACEi or ARB. It is reasonable to utilize similar monitoring strategies by measuring serum creatinine and serum potassium in patients treated with aliskiren.
Clonidine, guanfacine, and methyldopa lower BP primarily by stimulating α2-adrenergic receptors in the brain. This stimulation reduces sympathetic outflow from the vasomotor center in the brain and increases vagal tone. It is also believed that peripheral stimulation of presynaptic α2-receptors may further reduce sympathetic tone. Reduced sympathetic activity together with enhanced parasympathetic activity can decrease heart rate, CO, TPR, plasma renin activity, and baroreceptor reflexes. Clonidine is often used in resistant hypertension, and methyldopa is commonly used for pregnancy-induced hypertension.
Chronic use of a centrally acting α2-agonist results in sodium and water retention, which is most prominent with methyldopa. Low doses of clonidine and guanfacine can be used to treat hypertension without the addition of a thiazide. However, methyldopa should be given in combination with a thiazide to avoid the blunting of an antihypertensive effect that happens with prolonged use when used to treat chronic hypertension (but not in pregnancy). Sedation and dry mouth are common anticholinergic side effects that typically improve with chronic use of low doses, but they are more troublesome in older patients. As with other centrally acting antihypertensives, depression can occur, especially with high doses. The incidence of orthostatic hypotension and dizziness is higher than with other antihypertensive agents, so they should be used very cautiously in the elderly. Lastly, clonidine has a relatively high incidence of anticholinergic side effects (sedation, dry mouth, constipation, urinary retention, and blurred vision). Thus, it should generally be avoided for chronic antihypertensive therapy in older patients.
Abrupt cessation of a central α2-agonist may lead to rebound hypertension. This effect is thought to be secondary to a compensatory increase in norepinephrine release after abrupt discontinuation. In addition, other effects such as nervousness, agitation, headache, and tremor can also occur, which may be exacerbated by concomitant β-blocker use, particularly with clonidine. Thus, if clonidine is to be discontinued, it should be tapered. For patients who are receiving concomitant β-blocker therapy, the β-blocker should be gradually discontinued first several days before gradual discontinuation of clonidine.
Methyldopa can cause hepatitis or hemolytic anemia, although this is rare. Transient elevations in serum hepatic transaminases are occasionally seen with methyldopa therapy but are only clinically relevant if greater than three times the upper limit or normal. Methyldopa should be quickly discontinued if persistent increases in serum hepatic transaminases or alkaline phosphatase are detected because this may indicate the onset of fulminant life-threatening hepatitis. A Coombs-positive hemolytic anemia occurs in <1% of patients receiving methyldopa, although 20% exhibit a positive direct Coombs test without anemia. For these reasons, methyldopa has limited use in routine management of hypertension, except in pregnancy.
Direct Arterial Vasodilator
Hydralazine and minoxidil directly relax arteriolar smooth muscle resulting in vasodilation and BP lowering. They exert little to no venous vasodilation. Both agents cause potent reductions in perfusion pressure that activate baroreceptor reflexes. Activation of baroreceptors results in a compensatory increase in sympathetic outflow, which leads to an increase in heart rate, CO, and renin release. Consequently, tachyphylaxis (loss of antihypertensive effect) can develop with continued use. This compensatory baroreceptor response can be counteracted by concurrent use of a β-blocker.
All patients receiving hydralazine or minoxidil for chronic therapy should first receive both a thiazide and a β-blocker. Direct arterial vasodilators can precipitate angina in patients with stable ischemic heart disease unless the baroreceptor reflex mechanism is blocked with a β-blocker. Nondihydropyridine CCBs (diltiazem and verapamil) can be used as an alternative to β-blockers, but a β-blocker is preferred. The side effect of sodium and water retention is significant but is minimized by using a thiazide concomitantly.
One side effect unique to hydralazine is a dose-dependent drug-induced lupus-like syndrome. Hydralazine is eliminated by hepatic N-acetyltransferase. This enzyme displays genetic polymorphism, and “slow acetylators” are especially prone to develop drug-induced lupus with hydralazine. This syndrome is more common in women and is reversible on discontinuation. Drug-induced lupus may be avoided by using less than 200 mg of hydralazine daily. Because of side effects, hydralazine has limited clinical use for chronic management of hypertension. However, it is especially useful for patients with severe CKD and in kidney failure. Hydralazine, when used in combination with isosorbide dinitrate, has been shown to reduce the risk of CV events in black patients with HFrEF when added to a standard regimen of a diuretic, ACEi or ARB, and evidence-based β-blocker therapy.46
Minoxidil is a more potent vasodilator than hydralazine. Therefore, the compensatory increases in heart rate, CO, renin release, and sodium retention are even more dramatic. Due to significant water retention, a loop diuretic is often more effective than a thiazide in patients treated with minoxidil. A troublesome side effect of minoxidil is hypertrichosis (hirsutism), presenting as increased hair growth on the face, arms, back, and chest. Hypertrichosis usually ceases when the drug is discontinued. Other minoxidil side effects include pericardial effusion and a nonspecific T-wave change on the electrocardiogram. Minoxidil is reserved for resistant hypertension and for patients requiring hydralazine that experience drug-induced lupus.
Initial therapy with a combination of two antihypertensive drugs is recommended for patients with stage 2 hypertension particularly if BP is >20/10 mm Hg away from goal.1 Using a fixed-dose combination product is an option for these types of patients and has been shown to improve adherence. Initial two-drug combination therapy may also be appropriate for patients with multiple compelling indications for different antihypertensive agents. Moreover, combination therapy is often needed to control BP in patients who are already treated with drug therapy because most patients require two or more agents.1
Long-term safety and efficacy of initial two-drug therapy for hypertension has been evaluated in the ACCOMPLISH trial.88 This was a prospective, randomized, double-blind trial in 11,506 patients with hypertension and other CV risk factors. All of these patients either had stage 2 hypertension or were on antihypertensive drug therapy at enrollment. Patients were randomized to receive either benazepril-with-hydrochlorothiazide or benazepril-with-amlodipine as initial drug therapy. Treatment was titrated to a goal BP of <140/90 mm Hg for most patients and <130/80 mm Hg for patients with diabetes or CKD.
The trial was terminated early after a mean of 36 months because the incidence of CV events was 20% lower in the benazepril-with-amlodipine group compared with the benazepril-with-hydrochlorothiazide group. What is most important for clinical practice is that this trial established that initial two-drug therapy for stage 2 hypertension, as has been consistently recommended in guidelines dating back to 2003 (the JNC 7), was safe and highly effective in lowering BP. Mean BP measurements were 132/73 and 133/74 mm Hg in the benazepril-with-amlodipine and the benazepril-with-hydrochlorothiazide groups, respectively. However, rates of attaining a BP of <140/90 mm Hg were 75.4% and 72.4% (benazepril-with-amlodipine and benazepril-with-hydrochlorothiazide, respectively).
The ACCOMPLISH trial established initial two-drug antihypertensive therapy as an evidence-based strategy to treat hypertension. Clinicians should consider this study as justification for implementing initial two-drug therapy antihypertensive regimens in appropriate patients. Moreover, The ACCOMPLISH trial demonstrated that the combination of an ACEi with a dihydropyridine CCB was more effective in reducing CV events than the combination of an ACEi with hydrochlorothiazide. However, thiazides are very effective at lowering BP, particularly chlorthalidone and indapamide, especially when used in combination with other agents, and hydrochlorothiazide is available in many fixed-dose combination products.
Optimal Use of Combination Therapy
Clinicians should anticipate the need for combination therapy to control BP in most patients. Using low-dose combinations also provides greater reductions in BP compared with high doses of single agents, with fewer drug-related side effects.71 Contrary to popular myth, appropriately increasing the number of antihypertensive medications to attain goal BP values does not increase the risk of adverse effects. The American Society of Hypertension has recommended three categories of combination therapy (see “AMERICAN SOCIETY OF HYPERTENSION RECOMMENDATIONS FOR COMBINATION THERAPY” box).89 Preferred combinations are ideal for lowering BP, have complementary mechanisms of action, and use evidence-based first-line agents. Acceptable combinations may not provide all of the benefits that preferred combinations do, and may have additive side effect profiles. Less effective combinations are limited in their overall benefits, and should only be used when necessary, except when treating compelling indication. American Society of Hypertension Recommendations for Combination Therapy89
|Preferred ||Acceptable ||Less Effective |
|CCB (dihydropyridine)/β-blocker ||ARB/β-blocker |
|CCB/thiazide ||CCB (nondihydropyridine)/β-blocker |
|Thiazide/potassium-sparing diuretic ||Centrally acting agent/β-blocker |
Some combinations should be avoided when treating hypertension. As previously discussed, the ON-TARGET demonstrated that the use of an ACEi with an ARB in the management of hypertension resulted in no additional reduction in the incidence of CV events.90 Moreover, this combination resulted in a higher risk of adverse events that was also demonstrated in other trials. These same negative effects are seen when aliskiren is used in combination with an ARB.91 These combinations (using two RAAS blockers together) should be avoided in the management of hypertension.1 Other combinations such as a thiazide with a potassium-sparing diuretic, both of which appear to have overlapping mechanisms of action, should be implemented only to minimize side effects and not for additional BP lowering. The combination of two CCBs, a dihydropyridine with a nondihydropyridine, can provide additional BP lowering but has limited use in the routine management of most patients. Under no circumstance should two drugs from the exact same class of medications be used to treat hypertension.
Fixed-Dose Combination Products
Many fixed-dose combination products are commercially available, and many are generic (see Table 30-9). Most of these products contain a thiazide and have multiple dose strengths available. Individual dose titration is more complicated with fixed-dose combination products, but this strategy can reduce the number of daily tablets/capsules and can simplify regimens to improve adherence by decreasing pill burden. This alone may increase the likelihood of achieving or maintaining goal BP values and is a recommended strategy to improve adherence.1 Depending on the product, some may be less expensive to patients and health systems. Nonadherence rates are 24% lower when fixed-dose combination products are used to treat hypertension compared with using free drug components (separate pills) to treat hypertension.92
TABLE 30-9Fixed-Dose Combination Products
The cost of effectively treating hypertension is substantial, with estimated annual healthcare expenditures of approximately $2,000 more for patients with hypertension than without hypertension.93 The average annual direct and indirect cost of hypertension from 2013 to 2014 was $53.2 billion, with direct costs alone estimated to grow to $220.9 billion by 2035.4 Costs of care, though, are offset by savings that would be realized by reducing CV morbidity and mortality. Cost related to treating CV events (eg, MI, end-stage kidney failure) can drastically increase healthcare costs.
Antihypertensive drug costs are not a major portion of the total cost of hypertensive care. Most antihypertensives including an ACEi, an ARB, a CCB, and a thiazide are generic, with many available on discount formularies, including even generic fixed-dose combinations.
It is crucial to identify ways to control the cost of care without increasing the morbidity and mortality associated with uncontrolled hypertension. Using evidence-based pharmacotherapy will save costs. An ACEi, an ARB, a CCB, and a thiazide are all first-line treatment options in most patients without compelling indications, and are inexpensive, with few exceptions. Utilizing generic agents, either as monotherapy or in combination, is appropriate under nearly all circumstances in hypertension management. Use of once-daily and fixed-dose generic combination antihypertensives that are economical is preferred.1
Team-Based Collaborative Care
Team-based care for patients with cardiovascular disease is highly recommended in the comprehensive care of patients.1 A collaborative approach to management of hypertension is a proven strategy that improves goal BP attainment rates.1 Ideal patient care models are interprofessional and utilize physicians, pharmacists, nurses, and other healthcare professionals.
With the advent of healthcare reform, collaborative team-based approaches to chronic diseases are viewed as high-quality and cost-effective improvement modalities. Within these models, pharmacists have been proven to be an effective component of team-based models not only in community pharmacy or ambulatory clinic settings94 but also in community outreach sites such as black-owned barbershops.95 In addition to optimizing selection and implementation of antihypertensive drug therapy and increased attainment of goal BP, clinical interventions by pharmacists have been proven to reduce the risk of adverse drug events and medication errors in ambulatory patients with CV disease.96 Clinical pharmacists have a substantial effect in a wide variety of roles in clinical settings, largely through optimization of drug use, avoidance of adverse drug events, and transitional care activities focusing on medication reconciliation and patient education.97
Hypertensive Urgencies and Emergencies
Both hypertensive urgencies and emergencies are characterized by the presence of very elevated BP, typically >180/120 mm Hg.1 However, the need for urgent or emergent antihypertensive therapy must be determined based on the presence of acute or immediately progressing end-organ injury, not elevated BP alone. Urgencies are not associated with acute or immediately progressing end-organ injury, while emergencies are. Examples of acute end-organ injury include encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, acute renal failure, and eclampsia.
A common error with hypertensive urgency is implementing overly aggressive antihypertensive drug therapy. The classification terminology “urgency” has likely perpetuated this treatment. Hypertensive urgencies are ideally managed by adjusting maintenance therapy, by adding a new antihypertensive agent, by increasing the dose of a current medication, or by treating anxiety as applicable.1 Using this approach is preferred as it provides a more gradual reduction in BP. Very rapid reductions in BP to goal values should be discouraged due to potential risks of adverse events. Because autoregulation of blood flow in patients with hypertension occurs at a much higher range of pressure than in normotensive persons, the inherent risks of reducing BP too precipitously include cerebrovascular accidents, MI, and acute kidney failure. Hypertensive urgency requires BP reductions with oral antihypertensive agents to stage 2 over a period of several hours to days. All patients with hypertensive urgency should be reevaluated within and no later than 7 days (preferably after 1-3 days).
Acute administration of a short-acting oral antihypertensive (eg, captopril, clonidine, labetalol) followed by careful observation for several hours to assure a gradual reduction in BP is an option for treatment of hypertensive urgency. However, no data support this approach as being absolutely needed. Oral captopril is one of the agents of choice and can be used in doses of 25 to 50 mg at 1- to 2-hour intervals. The onset of action of oral captopril is 15 to 30 minutes, and a marked fall in BP is unlikely to occur if no hypotensive response is observed within 30 to 60 minutes. For patients with hypertensive rebound following withdrawal of clonidine, 0.2 mg can be given initially, followed by 0.2 mg hourly until the DBP falls below 110 mm Hg or a total of 0.7 mg clonidine has been administered. A single dose may be all that is necessary. Labetalol can be given in a dose of 200 to 400 mg, followed by additional doses every 2 to 3 hours.
Oral or sublingual immediate-release nifedipine has been used for acute BP lowering in the past but is dangerous. This approach produces a rapid reduction in BP. Immediate-release nifedipine should never be used for hypertensive urgencies due to risk of causing severe adverse events (eg, MI, stroke).
Hypertensive emergencies are rare situations that require immediate BP reduction with one of the parenteral agents listed in Table 30-10 to limit new or progressing end-organ damage (see Classification under Arterial BP above). The rate of BP reduction is dependent upon whether the patient has aortic dissection, severe preeclampsia or eclampsia, or pheochromocytoma with hypertensive crisis. In these life-threatening situations, patients should be cared for in the intensive care unit, and SBP should be reduced immediately to <140 mm Hg in the first hour, with additional BP lowering to <120 mm Hg for patients with an aortic dissection.1 For patients with a hypertensive emergency that do not have an aortic dissection, severe preeclampsia or eclampsia, pheochromocytoma with hypertensive crisis, the goal is not to lower BP to <130/80 mm Hg; rather, the initial target is a reduction in MAP of up to 25% within over the first hour. If the patient is then stable, BP can be reduced to 160/100-110 mm Hg within the next 2 to 6 hours.1 Precipitous drops in BP may lead to end-organ ischemia or infarction. If patients tolerate this reduction well, additional gradual decreases toward goal BP values can be attempted after 24 to 48 hours. The exception to this guideline is for patients with an acute ischemic stroke where maintaining an elevated BP is needed for a longer period.
TABLE 30-10Parenteral Antihypertensive Agents for Hypertensive Emergency ||Download (.pdf) TABLE 30-10 Parenteral Antihypertensive Agents for Hypertensive Emergency
|Medication ||Dose ||Onset (minutes) ||Duration (minutes) ||Adverse Effects ||Special Indications |
|Clevidipine ||1-2 mg/hr (32 mg/hr maximum) ||2-4 ||5-15 ||Headache, nausea, tachycardia, hypertriglyceridemia ||Most hypertensive emergencies except acute HF; caution with coronary ischemia; contraindicated in soy or egg allergy, defective lipid metabolism, and severe aortic stenosis |
|Enalaprilat ||1.25-5 mg IV every 6 hours ||15-30 ||360-720 ||Precipitous fall in pressure in high-renin states; variable response ||Acute left ventricular heart failure; avoid in acute myocardial infarction, eclampsia |
|Esmolol hydrochloride ||250-500 mcg/kg/min IV bolus, and then 50-100 mcg/kg/min IV infusion; may repeat bolus after 5 minutes or increase infusion to 300 mcg/min ||1-2 ||10-20 ||Hypotension, nausea, asthma, first-degree heart block, HF ||Aortic dissection; perioperative; avoid in patients treated with a β-blocker, bradycardic, or decompensated HF |
|Fenoldopam mesylate ||0.1-0.3 mcg/kg/min IV infusion ||<5 ||30 ||Tachycardia, headache, nausea, flushing ||Most hypertensive emergencies; caution with glaucoma |
|Hydralazine hydrochloride ||12-20 mg IV ||10-20 ||60-240 ||Tachycardia, flushing, headache, vomiting, aggravation of angina ||Eclampsia |
|10-50 mg intramuscular ||20-30 ||240-360 |
|Labetalol hydrochloride ||20-80 mg IV bolus every 10 minutes; 0.5-2 mg/min IV infusion ||5-10 ||180-360 ||Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension ||Most hypertensive emergencies except acute HF or heart block |
|Nicardipine hydrochloride ||5-15 mg/hr IV ||5-10 ||15-30, may exceed 240 ||Tachycardia, headache, flushing, local phlebitis ||Most hypertensive emergencies except acute HF; caution with coronary ischemia |
|Nitroglycerin ||5-100 mcg/min IV infusion ||2-5 ||5-10 ||Headache, vomiting, methemoglobinemia, tolerance with prolonged use ||Coronary ischemia |
|Sodium nitroprusside ||0.25-10 mcg/kg/min IV infusion (requires special delivery system) ||Immediate ||1-2 ||Nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication ||Most hypertensive emergencies; caution with high intracranial pressure, azotemia, or in chronic kidney disease |
The clinical situation should dictate which IV medication is used to treat hypertensive emergencies. Regardless, therapy should be provided in a hospital intensive care unit or emergency room setting with intra-articular BP monitoring. Table 30-10 lists special indications for agents that can be used.
Nitroprusside is widely considered the agent of choice for most cases, but it can be problematic for patients with CKD. It is a direct-acting vasodilator that decreases PVR but does not increase CO unless left ventricular failure is present. Nitroprusside can be given to treat most hypertensive emergencies, but in aortic dissection, propranolol should be given first to prevent reflex sympathetic activation. Nitroprusside is metabolized to cyanide and then to thiocyanate, which is eliminated by the kidneys. Therefore, serum thiocyanate levels should be monitored when infusions are continued for longer than 72 hours. Nitroprusside should be discontinued if the concentration exceeds 12 mg/dL (∼2 mmol/L). The risk of thiocyanate accumulation and toxicity is increased for patients with impaired kidney function. The use of nitroprusside is limited by a recent and significant increase in the cost of this agent.
IV nitroglycerin dilates both arterioles and venous capacitance vessels, thereby reducing both cardiac afterload and cardiac preload, which can decrease myocardial oxygen demand. It also dilates collateral coronary blood vessels and improves perfusion to ischemic myocardium. These properties make IV nitroglycerin ideal for the management of hypertensive emergency in the presence of myocardial ischemia and/or acute pulmonary edema. IV nitroglycerin is associated with tolerance when used over 24 to 48 hours and can cause a severe headache.
Fenoldopam, nicardipine, and clevidipine are newer agents. Fenoldopam is a dopamine-1 agonist. It can improve renal blood flow and may be especially useful for patients with kidney insufficiency. Nicardipine and clevidipine are dihydropyridine CCBs that provide arterial vasodilation and can treat cardiac ischemia similar to nitroglycerin, but they may provide more predictable reductions in BP.
The hypotensive response of hydralazine is less predictable than with other parenteral agents. Therefore, its major role is in the treatment of eclampsia or hypertensive encephalopathy associated with renal insufficiency.