The Washington Manual of Outpatient Internal Medicine, 2nd Ed.

6. Hypertension

Arielle Yang and Thomas M. De Fer

GENERAL PRINCIPLES

· Hypertension (HTN) is one of the most commonly encountered diseases in the outpatient setting, with an estimated prevalence rate of 30%.

· Starting from as low as 115/75 mm Hg, the mortality from cardiovascular disease (CVD) doubles for every increase of 20 mm Hg systolic or 10 mm Hg diastolic pressure, highlighting the tremendous burden that elevated blood pressure (BP) places on society as well as the importance of prompt recognition and treatment.¹

· Although considerable progress has been made in raising awareness of HTN over the last few decades, current recognition of those affected is far from adequate. Approximately 50% of patients with HTN have not achieved their treatment goal. Among these, an estimated 40% are not aware of their diagnosis and 90% have received health care in the past year.²

Definition

· For epidemiologic and practical reasons, HTN is currently defined as a systolic blood pressure (SBP) of ≥140 mm Hg and/or a diastolic blood pressure (DBP) of ≥90 mm Hg. This is based upon the average of two or more properly measured readings at each of two or more visits following an initial screen.³

· However, BP is a continuously distributed trait with a correspondingly variable risk of CVD, so defining HTN in terms of numbers is somewhat arbitrary. HTN can perhaps be better described as a progressive cardiovascular (CV) syndrome characterized by the presence of BP elevation to a level that places patients at increased risk for target organ damage in multiple vascular beds.

· HTN is further stratified into stages of severity based on both systolic and diastolic pressure. Table 6-1 provides the classification scheme for adults aged 18 and older from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7).³ Definitions and classification of HTN are not addressed specifically by the most recent JNC 8.⁴

· The term prehypertension was adopted to identify those at high risk of developing HTN in whom early intervention can decrease the rate of BP progression with age but does not denote a disease category.^3,5

TABLE 6-1 Classification of Blood Pressure for Adults

BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure.

Modified from Chobanian AV, Bakris GL, Black HR, et al. National High Blood Pressure Education Program Coordinating Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72.

Epidemiology

· An estimated 66.9 million people, with an overall prevalence rate of 30.4%, have HTN based on 2003–2010 National Health and Nutrition Examination Survey (NHANES) data, a substantial increase from earlier estimates of 50 million from 1988 to 1994.²

· The growing prevalence is directly related to an aging population and a higher rate of obesity.

· HTN is more common in dark-skinned individuals of African descent and those with a family history of HTN. The prevalence is higher in men than in women until the age of 60, after which women are affected in greater numbers.

· HTN is a major risk factor for the development of CVD, chronic kidney disease (CKD), and dementia, with most affected patients dying from ischemic heart disease.

· Reversible risk factors include prehypertension, being overweight or obese, excessive alcohol intake, a high-sodium low-potassium diet, and a sedentary lifestyle.

· Associated conditions include the metabolic syndrome, diabetes mellitus (DM), kidney disease, and obstructive sleep apnea (OSA).

Etiology

· Essential/primary hypertension

o The most common cause of HTN affecting approximately 95% of patients

o Thought to be due to a complex interplay of multiple factors including genetics, increased sympathetic and angiotensin II activity, insulin resistance, salt sensitivity, and environmental influences

· Secondary hypertension

o Affects a much smaller minority (about 5%) of patients.

o Secondary to a disease process with a specific identifiable structural, biochemical, or genetic defect resulting in elevated BP.

o Some of the more common examples include renovascular disease, renal parenchymal disease, endocrinopathies, side effect of other drugs, and OSA. These entities are described further in the “Special Considerations” section.

Screening

· Elevated BP is usually discovered in asymptomatic patients during routine office visits and should, therefore, be checked as part of every health care encounter.

· The U.S. Preventive Services Task Force strongly recommends HTN screening but the optimal screening interval for HTN is unknown.⁶ Current recommendations call for checking BP at least every 2 years in those with normal BP (<120/80 mm Hg) and annually for persons with prehypertension. Table 6-2 presents a suggested time frame for follow-up evaluations based on BP measurements.^3,7

· If systolic and diastolic categories are different, follow recommendations for the shorter follow-up.

· The schedule may be modified based on reliable information about past BP measurements, other CV risk factors, and target organ damage.

TABLE 6-2 Recommendations for Follow-Up Based on Initial Blood Pressure

Modified from Chobanian AV, Bakris GL, Black HR, et al. National High Blood Pressure Education Program Coordinating Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72.

DIAGNOSIS

· The diagnosis of HTN is established by documenting SBP of ≥140 mm Hg and/or DBP of ≥90 mm Hg, based on the average of two or more readings obtained on each of two or more office visits.

· A patient may be diagnosed on the basis of an elevated SBP alone, even if the DBP is normal (i.e., isolated systolic HTN).

· With extreme elevations of BP (>210/120 mm Hg), the diagnosis can usually be safely made without the need for serial evaluations. In these circumstances, one should focus on the evaluation of end-organ damage and treatment of hypertensive urgency or emergency as indicated (see “Hypertensive Urgencies and Emergencies”).

· After the diagnosis of HTN has been made, there are three major objectives:

o Assess lifestyle or other CV risk factors that may affect prognosis and guide treatment.

o Reveal a cause of secondary HTN (most often not present).

o Assess the presence or absence of target organ damage.

· The history, physical examination, and further diagnostic testing are the primary tools to achieve these objectives.

Clinical Presentation

History

· Determine additional risk factors that increase the risk for CV events: increased age (men >45, women >55), cigarette smoking, obesity (body mass index [BMI] >30 kg/m²), physical inactivity, dyslipidemia, DM, kidney disease, and family history of premature CVD (for men, age <55, for women, age < 65). Modifiable risk factors should be treated.

· Seek evidence of end-organ damage that may be either known or suggested by characteristic symptoms:

o Coronary artery disease (CAD) or prior myocardial infarction (MI) (angina or exertional dyspnea)

o Heart failure (HF) (symptoms of volume overload and/or dyspnea)

o Prior transient ischemic attack (TIA) or stroke (dementia or focal deficits)

o Peripheral artery disease (PAD, claudication)

o Renal disease

· Secondary HTN should be considered when BP becomes severely elevated acutely in a previously normotensive individual, at extremes of age (<20 or >50), or if refractory to treatment with multiple medications. Other symptoms that may be helpful include muscle weakness, palpitations, diaphoresis, skin thinning, flank pain, snoring, or daytime somnolence. See the “Secondary Hypertension” section.

· Conduct a thorough evaluation of the patient’s medications, as many agents have side effects of elevated BP. Common examples include oral contraceptives, nonsteroidal anti-inflammatory drugs (NSAIDs), and tricyclic antidepressants.

o Oral contraceptives induce sodium retention and potentiate the action of catecholamines.

o NSAIDs block the formation of vasodilating, natriuretic prostaglandins and interfere with the effectiveness of many antihypertensives.

o Tricyclic antidepressants inhibit the action of centrally acting agents (e.g., clonidine).

· Excess alcohol consumption and illicit substances such as cocaine can also raise BP.

Physical Examination

· Blood pressure measurement

o Optimal detection of HTN depends on proper technique.⁸

o BP should be measured while the patient is in the seated position with the arm supported at the heart level.

o The patient should have avoided caffeine, exercise, and smoking for at least 30 minutes prior to measurement.

o An appropriately sized cuff with the bladder encircling at least 80% of the arm circumference should be used to ensure accuracy.

o The cuff should be inflated rapidly to 20 to 30 mm Hg past the level where the radial pulse is no longer felt and then deflated at a rate of 2 mm Hg/second.

o The stethoscope should be placed lightly over the brachial artery.

o SBP should be noted at the sound of the brachial pulse (Korotkov phase I) and DBP at the disappearance of the pulse (Korotkov phase V).

o Two readings should be taken, ideally separated by at least 2 minutes.

o Elevated values should be confirmed in both arms. If there is a disparity due to a unilateral arterial lesion, the reading from the arm with higher pressure should be used.

· Ambulatory blood pressure monitoring

o In some situations, ambulatory blood pressure monitoring (ABPM) can be used to provide further information.³ With ABPM, patients wear automated, lightweight devices that obtain multiple BP measurements at specific intervals throughout a 24- to 48-hour period. It more effectively reflects a patient’s true diurnal variation in BP with lower values during sleep and higher values during wakefulness or activity.

o By ABPM HTN can be defined as an average awake BP >135/85 and average sleep BP >120/75.³

o Studies have suggested that values obtained with ABPM more closely correlate with end-organ complications than do values obtained in the physician’s office.⁹

o ABPM may be particularly useful in suspected cases of white coat HTN in which the anxiety of the physician encounter may falsely elevate BP while values outside of the office are often normal. The risk of CV events in patients with true white coat HTN is frequently debated but a meta-analysis of eight trials suggested there may be no excess risk over normotensive individuals.¹⁰

o Ambulatory monitoring may also reveal masked HTN and nighttime nondippers. Masked HTN indicates patients with normal in-office BP but hypertensive readings during ABPM, and has a prevalence on the order of 10%.¹¹ It is associated with increased CV risk.^10,12 Currently, it is not clear whom should be screened for masked HTN. Patients receiving treatment for HTN may also display masked HTN with ABPM. Nocturnal HTN and nondipping (i.e., BP not falling by ≥10% during sleep) are also associated with increased CV events.^13,14

o ABPM may also be helpful in guiding treatment decisions in patients with borderline HTN, resistant HTN, or symptoms suggestive of hypotension on treatment.³

o ABPM is often impractical due to cost and poor reimbursement. Home blood pressure monitoring (HBPM) with self-measurement of BP may serve as a more practical alternative in patients whose values are consistently <130/80 mm Hg despite an elevated office value.³ It is also recommended as an adjuvant to HTN management.¹⁵

· After obtaining accurate BP measurements, the physical examination should be tailored to evaluate the presence and severity of target end-organ damage and any features that may suggest secondary HTN.

· Cardiopulmonary exam: S4 gallop suggesting left ventricular hypertrophy (LVH), murmurs, or rales suggesting HF.

· Funduscopic exam: papilledema, arteriolar narrowing, cotton wool spots, and microaneurysms.

· Vascular exam: bruits of major arterial vessels (carotids, femorals, and aorta), asymmetric or diminished distal pulses.

· Neurologic exam: altered mental status or focal findings suggestive of prior stroke.

· Endocrine: elevated BMI, thyroid enlargement, and Cushingoid features (e.g., buffalo hump, striae, and skin thinning).

Diagnostic Testing

· Routine laboratory tests recommended before initiating therapy include serum electrolytes, blood urea nitrogen (BUN), creatinine, blood glucose, hematocrit, lipoprotein profile, thyroid-stimulating hormone, and urinalysis.

· Measurement of microalbuminuria is recommended in those with DM or renal disease but is otherwise elective and may add to the overall assessment of CV risk.^16–18

· An ECG should be obtained in all patients to assess for LVH and/or signs of previous infarct. Although echocardiography is more sensitive at diagnosing LVH, it is not recommended in all patients.

· A more detailed workup can be pursued for features suggestive of a secondary cause of HTN. Some of these are described in Table 6-3.

TABLE 6-3 Causes of Secondary Hypertension

CPAP, continuous positive airway pressure; CAD, coronary artery disease; PAD, peripheral arterial disease; CKD, chronic kidney disease; HF, heart failure; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; MRA, magnetic resonance angiography; CTA, computed tomographic angiography; BUN, blood urea nitrogen; PRA, plasma renin activity; PAC, plasma aldosterone concentration; HTN, hypertension; MIBG, metaiodobenzylguanidine; ACTH, adrenocorticotropic hormone; BP, blood pressure.

TREATMENT

· The goal of antihypertensive therapy is to reduce the morbidity and mortality of CVD attributable to HTN.

· Patient education is an essential component of the treatment plan and promotes better adherence. Physicians should stress the following:

o Lifelong treatment is often required.

o Symptoms are an unreliable gauge of severity (despite many patients’ claims that they can “feel” when their BP is high).

o Prognosis improves with effective management.

o The importance of therapeutic lifestyle changes.

o Adherence to medication therapy is critically important.

· All patients with prehypertension or HTN should be counseled regarding therapeutic lifestyle changes.^3,19,20 See “Other Nonpharmacologic Therapy”.

· For the general population of patients <60 years old the JNC 8 BP goal is <140/90. This does not differ from the JNC 7 recommendations.^3,4

· For the general population of patients ≥60 years old the new JNC 8 goal is <150/90. The prior JNC 7 goal had been <140/90. The JNC believes that the evidence most strongly support the SBP goal of <150 and points out that some data suggest that <140 adds no additional benefit.^3,4,21–24

Medications

· Medication treatment is generally considered appropriate/indicated for.⁴

o Patients <60 years with SBP >140 and/or DBP >90.

o Patients ≥60 years with SBP >150 and/or DBP >90.

· Starting two drugs in patients with more marked elevation in BP (<60 years >160/100, ≥60 years >170/100) is reasonable.³

· Many factors should be taken into consideration when initiating drug therapy including the following: evidence of improved clinical outcomes, comorbid diseases and other CV risk factors, demographic differences in response, affordability, lifestyle issues, and the likelihood of adherence.

· There is a high interpatient variability in response, with many patients responding well to one drug class but not to another.

· The amount of BP reduction rather than the specific antihypertensive drug is the major determinant in reducing CV risk in hypertensive patients.^25,26 However, this may not be the case with β-blockers and certain medication combinations.

· In the general non-Black (i.e., lacking specific overriding indications) population, initial medication management should include a thiazide diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB).⁴

· In the general Black population (i.e., lacking specific overriding indications), initial management should include a thiazide diuretic or CCB.^4,27,28

· β-Blockers should not be considered first-line therapy in patients without evidence-based indications due to the lack of consistent data supporting an independent positive effect on CV morbidity and mortality and relatively less stroke protection compared to other first-line agents.^4,29–31

· While the ALLHAT trial did demonstrate greater benefit of chlorthalidone (CTDN) in terms of HF, the JNC 8 did not conclude that this finding was compelling enough to recommend thiazide diuretic above the other first-line agents.^4,27

· Many patients have specific indications for particular antihypertensive agents based on other comorbidities (Table 6-4).³ Data regarding these indications are discussed in the appropriate sections below.

· A patient with mild HTN who is relatively unresponsive to one drug has an almost 50% likelihood of responding to a second drug, so trials of different agents are warranted before moving to combination therapy.³²

· Many patients will not reach treatment goal BP on one drug.^3,4

· The typical decrease in BP with a single agent is approximately 8 to 15 mm Hg systolic and 8 to 12 mm Hg diastolic.^33,34 Most patients with HTN, however, will eventually require two or more medications.^3,4

· Combination therapy is appropriate if BP cannot be controlled with a single agent, in patients with stage 2 HTN, and in patients with specific indications for multiple agents (Table 6-4).

· Thiazide diuretics, CCBs, ACE inhibitors, and ARBs are all appropriate add-on agents.⁴

· Fixed-dose combination pills offer the advantage of convenience that may improve adherence but sometimes at a higher cost to the patient and with less flexibility in adjusting doses.

TABLE 6-4 Indications for Individual Drug Classes

^aCombination therapy frequently required.

^bFirst-choice agent according to the American Diabetes Association.

^cIn patients with left ventricular dysfunction.

^dLoop rather than thiazide diuretic.

^eParticularly for patients with albuminuria ≥30 mg/day (or albumin/creatinine ratio ≥30 mg/g).

ACE-I, angiotensin-converting enzyme inhibitor; Aldo ANT, aldosterone antagonist; ARB, angiotensin receptor blocker; BB, β-blocker; CCB, calcium channel blocker; HDZ, hydralazine; NIT, nitrate.

Data from Chobanian AV, Bakris GL, Black HR, et al. National High Blood Pressure Education Program Coordinating Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72.

Specific Patient Populations

· Diabetes

o HTN occurs more frequently in diabetics compared with nondiabetics. These two conditions together significantly increase a patient’s risk of developing both major CV events and microvascular disease.

o The JNC 8 BP treatment goals are the same a nondiabetics (i.e., <140/90).⁴

o The American Diabetes Association (ADA) 2014 standards of care, however, recommend a goal of <140/80.³⁵ An SBP of <130 is suggested for some patients (e.g., relatively young) if this can be attained without significant treatment burden.³⁵

o The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated a reduction in mortality (15%), MI (11%), and retinopathy/nephropathy (13%) for every 10 mm Hg reduction in SBP.³⁶

o The JNC 8 recommendation regarding which particular drug to use/start in diabetics is the same as for nondiabetics, based on the lack of difference in CV outcomes.⁴

o The ADA specifically recommends that an ACE inhibitor or an ARB should be a component of antihypertensive treatment given their ability to retard loss of renal function and proteinuria independent of antihypertensive effects.^35,37–40

o Most hypertensive diabetics will require more than one antihypertensive to achieve goal BP.

· Ischemic heart disease

o β-Blockers reduce mortality following MI and should be initiated in all patients regardless of left ventricular (LV) function. Immediate therapy should be avoided in acute MI patients with signs HF or risk factors for cardiogenic shock.^41–44

o β-Blockers without intrinsic sympathomimetic activity are preferred; therefore, acebutolol and pindolol should not be used. When LV function is impaired (without evidence of unstable HF or shock), β-blockers with proven benefit in HF should be used (i.e., metoprolol, carvedilol, and bisoprolol).^41,42,44

o ACE inhibitors also have mortality benefit in patients following an MI, especially those with impaired LV function.^{41,42,45–48} An ARB may be substituted for patients intolerant to ACE inhibitors. Combined ACE inhibitor and ARB does not have further benefit and is associated with more adverse events. Perindopril has also been shown to decrease CV events in patients with stable CAD.⁴⁹

o CCBs may be used if β-blockers are contraindicated or if additional BP or angina control is necessary. A long-acting dihydropyridine is recommended to limit the risk of heart block, bradycardia, and reflex tachycardia.

· Heart failure

o ACE inhibitors, ARBs, β-blockers, aldosterone antagonists, and the combination of hydralazine and nitrates have all been shown to have mortality benefit in HF, depending on disease severity.^50–58

o Extended release metoprolol succinate, carvedilol, and bisoprolol all have proven benefit and are the preferred β-blockers.

o The addition or an ARB to ACE inhibitor therapy may be useful in some patients but patients should be monitored carefully for hyperkalemia, worsening renal function, and hypotension.^59,60 The concomitant use of an ACE inhibitor, ARB, and aldosterone antagonist is not recommended.

o Loop diuretics constitute an important aspect of fluid management and are typically an essential part of the patient’s regimen.

o While CCBs may cause adverse effects due to their negative inotropic properties, long-acting dihydropyridines can provide additional BP control with less potential for myocardial depression than with verapamil and diltiazem.

· Chronic kidney disease

o The JNC 8 BP goal for patients with CKD is the same as for the general population, <140/90.⁴

o The Kidney Disease: Improving Global Outcomes (KDIGO) Working Group, however, recommends a more strict goal of <130/80 for patients with CKD not on dialysis and with albuminuria ≥30 mg/day (or albumin/creatinine ratio ≥30 mg/g or proteinuria ≥150 mg/day). Data most strongly support this goal for those with albuminuria ≥300 mg/day. The more lenient goal of <140/90 is recommended by KDIGO when albuminuria is <30 mg/day.⁶¹

o The National Kidney Foundation accepts these recommendations as reasonable but points out the lack of quality supporting data for the more stringent goals, particularly in those with moderate albuminuria (i.e., 30 to 300 mg/g).⁶²

o KDIGO recommends that an ACE inhibitor or an ARB are first-line therapy in patients with albuminuria ≥30 mg/day (or albumin/creatinine ratio ≥30 mg/g), particularly in those with concurrent DM.^{36–40,63–65} Again the data most strongly support this recommendation in those with albuminuria ≥300 mg/day.

o While adding an ARB to an ACE inhibitors reduces proteinuria more, data indicate that this may worsen outcome.^66,67

· Stroke

o During the acute phase of an ischemic stroke (at least the first 24 hours), BP is often increased and is generally not treated unless it is severely elevated (>220/120 mm Hg) or there is other ongoing end-organ damage (e.g., myocardial ischemia, HF, dissection, acute kidney injury [AKI], encephalopathy).⁶⁸ An important exception is for patients who are to receive fibrinolytic therapy, in which case the BP should be lowered to <185/110 mm Hg and then to <180/105 mm Hg once it has been given. When to start or resume chronic antihypertensive therapy after an acute ischemic stroke is a matter of controversy; in most patients it is reasonable to initiate treatment after the first 24 hours.

o The acute management of BP in intracerebral hemorrhage is more complex and the BP can be extremely high in this circumstance. Guidelines recommend treatment for SBP >180 mm Hg (mean arterial pressure >130 mm Hg), with the aggressiveness of therapy and monitoring dependent on the degree of elevation and the concern for increased intracranial pressure.⁶⁹ With an acute subarachnoid hemorrhage antihypertensive treatment is very generally recommended to decrease SBP <160 mm Hg.⁷⁰

o Treatment of HTN to reduce the risk of recurrent stroke or TIA is clearly indicated.^71–73 The PROGRESS trial demonstrated a reduction in recurrent stroke and all CV events in patients treated with perindopril and indapamide compared to placebo. The degree of reduction was dependent on the degree of BP lowering, which was most notable in the combined therapy patients.⁷⁴ Some patients had preexisting HTN and others did not. The same has been shown for indapamide alone.⁷² A very large trial found no such difference with telmisartan versus placebo but the degree of achieved BP reduction was very small.⁷⁵ Whether the class of drug used is as or more important than the degree of BP lowering has yet to be clearly determined, particularly for combination therapy. Both the JNC 8 and the American Stroke Association (ASA) recommend initiating treatment in patients with a prior stroke or TIA for BP ≥140/90 mm Hg and for a goal BP of <140/90 mm Hg.^4,73

· Black patients

o HTN is more common, is more severe, and has a higher morbidity in Blacks compared with non-Hispanic Whites.

o Blacks have lower plasma renin levels, increased plasma volume, and higher peripheral vascular resistance (PVR) compared with non-Black patients.

o Dietary sodium reduction may be more effective in this population with a greater decrease in BP compared with other demographic groups.^76,77

o The JNC 8 does not make a specific BP target recommendations based solely on race and, therefore, treatment goals are the same as for non-Blacks.

o The 2010 International Society on Hypertension in Blacks (ISHIB) Consensus Statement recommends a goal of <135/85 for those with no evidence of end-organ damage, preclinical CVD, or overt CVD. A goal of <130/80 is recommended for Blacks with evidence of end-organ damage, preclinical CVD, or a history of CV events. In this context, end-organ damage was defined as albumin/creatinine ratio >200 mg/g, estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m², or ECG or echocardiographic evidence of LVH. CV events were defined as HF, CAD, MI, PAD, stroke, TIA, or abdominal aortic aneurysm. Preclinical CVD was defined as metabolic syndrome, Framingham risk >20%, prediabetes, or DM.²⁸

o JNC 8 recommends either a thiazide diuretic or CCB as first-line therapy for Blacks, including those with DM.^4,27 ISHIB emphasizes the common necessity of combined therapy in Blacks.²⁸

o While Blacks in general have less of a BP reduction with ACE inhibitors and ARBs, they can still be very effective, particularly when combined with a diuretic or dihydropyridine CCB.^7,28 The ACE inhibitor and CCB (rather than thiazide diuretic) combination may be particularly effective at reducing CV outcomes.⁷⁸

· Older patients

o HTN becomes much more common with advancing age (>60), particularly isolated systolic HTN (i.e., SBP >140 and DBP <90). SBP may be a stronger predictor of CV events than DBP.

o Data from clinical trials clearly support treating HTN in older patients.^21–24,79

o In elderly patients starting with lower doses and titrating slowly is, in general, reasonable advice. Care should be taken when increasing medications to avoid causing orthostatic hypotension and its symptoms. Following the standing BP may be helpful.⁸⁰

o When treating isolated systolic HTN it is generally agreed that there is no increased risk in lowering the DBP until it is <60.⁷

o Thiazide diuretics, long-acting dihydropyridine CCBs, and ACE inhibitors/ARBs are all reasonable choices for initial therapy in older patients.⁴

o The effectiveness of antihypertensive treatment in frail older patients is unknown.

Specific Drug Classes

· Thiazide diuretics

o Thiazides commonly used for HTN include hydrochlorothiazide (HCTZ), CTDN, and indapamide. They are a reasonable first choice for most patients.⁴

o Thiazides block sodium reabsorption at the distal convoluted tubule by inhibition of Na-Cl cotransporter, thereby decreasing plasma volume. Plasma volume, however, stabilizes after 2 to 3 weeks of therapy and partially returns to the pretreatment level. Therefore, the actual mechanism of sustained BP reduction is uncertain but may be due to a decrease in vascular resistance.

o CTDN is thought to be 1.5 to 2 times more potent than HCTZ and has a much longer half-life.

o They may be particularly effective in Blacks and the elderly who have a greater tendency to be sodium sensitive but are less effective in patients with renal insufficiency (eGFR <30 mL/minute/1.73 m²). In the latter case, a loop diuretic may be more appropriate.

o Multiple trials have shown thiazides to be effective in lowering BP, preventing initial and subsequent strokes, and reducing CV mortality.^21,27 These data are largely driven by the use of CTDN in the ALLHAT trial, while the data supporting a reduction in CV events with HCTZ are minimal.²⁷

o There is no randomized prospective trial data that specifically and directly compares the effectiveness of CTDN and HCTZ. A large network meta-analysis indirectly compared the two drugs and found CTDN to be superior in preventing CV events, even when the achieved SBP reduction was the same.⁸¹ Conversely, a large observational cohort did not find a difference in CV outcomes but did demonstrate a greater risk of hypokalemia with CTDN.⁸²

o The results of the ACCOMPLISH Trial indicate that the combination of HCTZ plus benazepril is inferior to amlodipine plus benazepril.⁷⁸ Given that many patients require combination therapy to achieve BP goals, these results could call into question the first-line drug of choice status of thiazides, particularly HCTZ, as CTDN was not studied in this trial.

o Side effects include electrolyte abnormalities (hypokalemia, hypomagnesemia, hypercalcemia, and hyperuricemia), muscle cramps, dyslipidemia, and glucose intolerance. Electrolyte monitoring is warranted during initiation, dosage changes, and occasionally when on stable treatment.

· Potassium-sparing diuretics

o Spironolactone and eplerenone inhibit the action of aldosterone by blocking the mineralocorticoid receptors in the cortical collecting ducts. Eplerenone is far more selective than spironolactone and does not have antiandrogenic or progestogenic effects. Amiloride and triamterene block the epithelial sodium channel and inhibit the reabsorption of sodium and secretion of potassium in the collecting ducts.

o Spironolactone and eplerenone are specifically indicated for patients with HF and reduced LV function after MI to improve morbidity and mortality.^55,58,83

o Patients with primary hyperaldosteronism who refuse or are not candidates for surgery can be treated with potassium-sparing diuretics. Spironolactone and eplerenone have the advantage of fully blocking the systemic effects of aldosterone rather than counteracting its effect only in the collecting ducts.

o Potassium-sparing diuretics are sometimes added to thiazides to offset the hypokalemic effect of the latter.

o All potassium-sparing diuretics can cause hyperkalemia and monitoring of potassium and renal function is advisable, particularly in patients with DM and/or CKD. Spironolactone can cause gynecomastia, decreased libido, and impotence in men and mastodynia and amenorrhea in women.

· Loop diuretics

o Loop diuretics inhibit sodium resorption by blocking the Na-K-Cl cotransporter in the ascending loop of Henle and include furosemide, bumetanide, torsemide, and ethacrynic acid. Ethacrynic acid does not contain a sulfa moiety and can be used in those with a sulfa allergy.

o Short-acting loop diuretics should not generally be considered antihypertensive agents in patients without CKD.

o They are appropriate antihypertensives for patients with HTN and eGFR <30 mL/minute/1.73 m² because hypervolemia is often an important factor.

o Side effects include electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia, and hyperuricemia), ototoxicity (less common with oral rather than intravenous), and glucose intolerance.

· ACE inhibitors

o Commonly used ACE inhibitors include benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

o As the name clearly implies, these drugs inhibit ACE leading to a decreased conversion of angiotensin I to angiotensin II, which reduces vasoconstriction, reduces aldosterone secretion, promotes natriuresis, and increases vasodilatory bradykinins.

o ACE inhibitors are appropriate initial therapy in most patients.⁴

o ACE inhibitors are considered first-line therapy in patients with HF or asymptomatic LV dysfunction, prior MI or high risk for CAD, DM, and CKD with moderate-to-severe albuminuria.^{36–38,45–47,51,63,65,84,85}

o They work well in combination with other agents, particularly diuretics, due to the activation of the renin-angiotensin system (RAS). As noted above, however, the results of the ACCOMPLISH Trial indicate that the combination of benazepril plus HCTZ is inferior to benazepril plus amlodipine.⁷⁸ CTDN was not studied in this trial.

o While adding an ARB to an ACE inhibitor further reduces proteinuria, data indicate that this may worsen outcome.^66,67

o ACE inhibitors are absolutely contraindicated in pregnancy.

o Side effects include hyperkalemia, orthostatic hypotension, cough, angioedema, and worsening renal function. However, an increase in serum creatinine is expected in most patients and up to 30% is acceptable and not a reason to discontinue therapy.

· ARBs

o The ARBs include candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan. These drugs directly block angiotensin II receptors resulting in vasodilation. They do not inhibit the breakdown of bradykinin and are much less likely to cause cough.

o ARBs are appropriate as initial therapy in most patients and generally effective in the same clinical settings as an alternative to ACE inhibitors.^{39,40,48,56,57}

o ARBs may be specifically beneficial in patients with LVH.³¹

o While adding an ARB to an ACE inhibitor further reduces proteinuria, data indicate that combined therapy does not improve CV outcome and may worsen renal outcome.^66,67

o ARBs are absolutely contraindicated in pregnancy.

o Side effects are similar to those of ACE inhibitors and include hypotension and a lower incidence of cough and angioedema.

· Direct renin inhibitors

o Aliskiren binds the active site of renin and inhibits the conversion of angiotensinogen to angiotensin I and subsequently dramatically reducing the levels of angiotensin II and aldosterone.

o Aliskiren is effective at lowering BP and has been studied as monotherapy and in combination with other drugs.^86–88

o One study showed that the addition of aliskiren to losartan in patients with diabetic nephropathy may further reduce albuminuria.⁸⁹ A subsequent randomized controlled trial in a much larger but similar population was terminated early due to a trend toward more stroke, hypotension, hyperkalemia, and a lack of benefit on CV and renal outcomes.⁹⁰

o At present, there are no long-term studies demonstrating a reduction in long-term hard CV or renal outcomes with aliskiren. It should not be used as first-line therapy.

o Side effects include hyperkalemia, decreased renal function, diarrhea, and cough.

· Calcium channel blockers

o CCBs selectively block the slow inward calcium channels in vascular smooth muscle causing arteriolar vasodilation.

o Long-acting dihydropyridine CCBs (e.g., amlodipine, felodipine, isradopine, nifedipine) are most commonly used for HTN while the nondihydropyridine CCBs (e.g., verapamil and diltiazem) are used for atrial fibrillation rate control and angina. CCBs are also indicated for coronary vasospasm or Raynaud phenomenon, and supraventricular arrhythmias.

o CCBs are appropriate as an initial treatment of HTN in most patients.^4,27

o They may be particularly effective in older patients with isolated systolic HTN and Blacks.^3,27,28

o As a class, CCBs have no significant effect on glucose tolerance, electrolytes, or lipid profiles and are not adversely affected by NSAIDs.

o Side effects include flushing, headache, dependent edema, gingival hyperplasia, and esophageal reflux.

· β-Blockers:

o β-Blockers competitively inhibit the effects of catecholamines at β receptors to decrease heart rate and cardiac output. Individual drugs have variable selectivity for β₁ and β₂ receptors. β₁ receptors are located mainly in the heart and kidneys. β₂ receptors are found in the lungs, vascular smooth muscle (causing vasodilation), gastrointestinal (GI) tract, uterus, and skeletal muscle. Some β-blockers also have antagonistic effects on α₁receptors. They also decrease plasma renin and release vasodilatory prostaglandins. The precise mechanism of sustained BP reduction, however, is uncertain.

o The nonselective β-blockers antagonize both β₁ and β₂ receptors and include propranolol, timolol, and nadolol. There is some risk of bronchospasm in patients with chronic obstructive pulmonary disease (COPD) or reactive airway disease. There is a theoretical possibility of hypoglycemia and blunting of the adrenergic response to hypoglycemia.

o Cardioselective β-blockers primarily act on β₁ receptors but lose some selectivity at higher doses. Examples include atenolol, bisoprolol, esmolol, and metoprolol. They seem to have less risk of inducing bronchospasm.

o Some β-blockers are said to have intrinsic sympathomimetic activity including acebutolol and pindolol. They exert low-level agonist activity while simultaneously antagonizing the site. Acebutolol is β₁-selective and pindolol is nonselective. These drugs may be useful in patients with excessive bradycardia but do not have demonstrated benefit in patients post-MI.

o The mixed α- and β-blockers labetalol and carvedilol have antagonist effects at both types of adrenergic receptors. Both have vasodilating properties through α₁-receptor blockade.

o Nebivolol is a new vasodilating β-blocker with and additional unique mechanism of action—potentiating nitric oxide (NO).

o The vasodilating β-blockers may be preferential to conventional nonselective β-blockers based on the latter being associated with inferior outcomes, an increased rate of stroke, and an increased risk of developing DM.²⁹On the other hand, it is important to note that to date there are no long-term outcome trials of vasodilating β-blockers used solely for the treatment of HTN.

o β-Blockers are no longer considered appropriate first-line agents for patients without compelling indications (e.g., MI or HF) due to the lack of data supporting an independent positive effect on morbidity and mortality.^4,29,30

o β-Blockers reduce mortality following MI and should be initiated in all patients regardless of left ventricular (LV) function. β-blockers without intrinsic sympathomimetic activity are preferred. When LV function is impaired (without evidence of unstable HF or shock), β-blockers with proven benefit in HF should be used (i.e., metoprolol, carvedilol, and bisoprolol).^41–43

o β-blockers have been clearly shown to have mortality benefit in HF, particularly metoprolol, carvedilol, and bisoprolol.^52–54

o β-blockers are also indicated for the treatment of tachyarrhythmias and angina.

o Side effects of β-blockers include fatigue, nausea, dizziness, heart block (especially when used with CCBs), worsening of HF, dyslipidemia, erectile dysfunction, and bronchospasm. Abrupt withdrawal can precipitate angina and elevation of BP because of the increase in adrenergic tone with chronic β-blocker use.

· α₁-Blockers:

o Prazosin, terazosin, and doxazosin block α₁ receptors on vascular smooth muscle cells, impairing catecholamine-induced vasoconstriction.

o α₁-Blockers are less efficacious than thiazides, CCBs, and ACE inhibitors as monotherapy based on the ALLHAT and are not recommended as first-line therapy.²⁷

o They are characterized by a first-dose effect with a larger decrease in BP than subsequent doses making use before bedtime more appropriate than the morning.

o They may decrease urinary symptoms in patients with prostate enlargement.

o Side effects include orthostatic hypotension, GI distress, and drowsiness.

· Centrally acting adrenergic agonists

o Clonidine and methyldopa stimulate α₂ receptors in the central nervous system leading to decreased peripheral sympathetic tone, PVR, heart rate, and cardiac output. Both are effective antihypertensives, but there are no long-term outcome data supporting either drug.

o Clonidine can be quite useful for hypertensive urgencies. Refer to the Hypertension Urgencies and Emergencies section.

o Abrupt cessation can precipitate an acute withdrawal syndrome characterized by tachycardia, diaphoresis, and severe elevations in BP.

o Methyldopa is safe in pregnancy.

o Side effects include bradycardia, sedation, orthostatic hypotension, depression, and sexual dysfunction. Methyldopa is associated with a lupus-like syndrome.

· Other sympatholytic agents such as reserpine, guanethidine, and guanadrel are no longer considered first- or second-line therapy because of their significant side effect profiles and the availability of more effective and much better-tolerated drugs.

· The so-called direct-acting vasodilators are hydralazine and minoxidil.

o These agents hyperpolarize arteriolar smooth muscle by activating gated potassium channels to produce direct relaxation and, therefore, vasodilation. Hydralazine requires the presence of NO to be functional and minoxidil contains a NO moiety.

o While these are potentially potent antihypertensive agents, there are no randomized clinical trials demonstrating improvements in CV morbidity and mortality with either drug when used specifically for HTN.Because of this, both are second-line therapy. Additionally, they have the potential for more frequent and significant side effects.

o Hydralazine plus nitrate improves mortality in patients with HF compared to placebo.⁵⁰ Further evidence indicates that ACE inhibitor therapy is more beneficial than the combination of hydralazine and nitrate in HF patients.⁹¹ In Blacks, the addition of hydralazine and nitrate to standard HF therapy (including RAS blockade and β-blockers) further improves mortality.⁹² Whether these effects are ethnically specific is unresolved. Care should be taken not to conflate these results with the use of hydralazine strictly as an antihypertensive. Additionally, oral nitrates are not appropriate for use as an ongoing BP-lowering agent.

o Both hydralazine and minoxidil may lead to reflex sympathetic hyperactivity and fluid retention that makes concomitant treatment with a diuretic and/or β-blocker desirable.

o Side effects of hydralazine include headache, tachycardia, orthostatic hypotension, GI distress, and a lupus-like syndrome. Minoxidil can lead to weight gain, hirsutism, hypertrichosis, ECG abnormalities, and pericardial effusions.

Other Nonpharmacologic Therapy

· Therapeutic lifestyle changes described in Table 6-5 should be instituted in all patients with HTN and prehypertension.^3,7,19,20 These represent a critical component of both prevention and management of those on drug therapy.

· Therapeutic lifestyle changes may be employed as sole therapy for 6 to 12 months to manage stage 1 HTN in the absence of DM, end-organ damage, evidence of CVD, or multiple other risk factors.^3,7,19

· Weight loss results in a reduction of SBP on the order of 1 mm Hg/kg. Put another way, a 5% weight loss results in about a 3 mm Hg reduction in SBP.^93–96 Orlistat and sibutramine increase weight loss but the former my increase BP.⁹³

· Exercise: Moderate- to vigorous-intensity aerobic activity 3 to 4 sessions/week, 40 minutes/session results in a 2 to 5 and 1 to 4 mm Hg reduction in SBP and DBP, respectively, independent of weight loss.²⁰

· Diet

o Reducing sodium levels decreases BP in some individuals but often enhances the antihypertensive effects of medications. Sodium intake should be restricted to 1.5 to 2.4 g/day (3.75 to 6 g sodium chloride). This degree of restriction may reduce SBP by 2 to 7 mm Hg.²⁰

o The Dietary Approaches to Stop Hypertension (DASH) diet and a Mediterranean diet pattern may be recommended.^20,97 The DASH diet consists of consuming a diet rich in fruits, vegetables, legumes, and low-fat dairy products with a reduced content of saturated and total fat. Adding sodium limitation to the DASH diet augments BP reduction.⁷⁶

o There is no universal definition of the Mediterranean dietary pattern. In general, it entails consuming a diet higher in fresh fruits, vegetables, whole grains, omega-3–rich fish, nuts, and avoiding red meat and higher-fat dairy products (e.g., butter). Olive oil is the typical fat. It also often includes moderate red wine consumption.

· Cessation of tobacco smoking is advised for overall CV health but does not reduce basal BP.

· Alcohol intake should be limited to ≤2 drinks/day for men and ≤1 drink/day for women and smaller men. Restricting alcohol to these levels can reduce SBP by 2 to 4 mm Hg.²⁰ One drink is equivalent to 12 oz beer (350 mL), 5 oz wine (150 mL), or 1.5 oz 80-proof whiskey (45 mL).

· Although relieving stress may improve one’s overall health, no studies have successfully demonstrated a link between stress reduction and a sustained reduction in BP.

TABLE 6-5 Lifestyle Modifications to Prevent and Reduce Hypertension

DASH, Dietary Approaches to Stop Hypertension.

Modified from Chobanian AV, Bakris GL, Black HR, et al. National High Blood Pressure Education Program Coordinating Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560–72.

SPECIAL CONSIDERATIONS

Resistant Hypertension

· Resistant HTN is defined as the persistent elevation of BP above goal despite the concurrent use of antihypertensive agents from three different classes, including a diuretic. This also includes BP that is adequately controlled on a four-drug regimen (i.e., controlled resistant HTN).^7,98 SBP is typically harder to control than DBP. Not surprisingly, patients with resistant HTN have worse CV outcomes.

· The term refractory HTN refers to those patients who remain uncontrolled despite all maximal medical therapy (prescribed and taken) and lifestyle modification.

· The exact prevalence of resistant HTN is unknown, but clinical trials and surveys suggest that it is a common phenomenon occurring in an estimated 20% to 30% of the population being treated for HTN.^98,99

· Patient characteristics associated with resistant HTN include higher baseline BP, older age, LVH, CKD, DM, obesity, high sodium intake, female gender, and Black ethnicity.^98–100

· Resistant HTN should be distinguished from so-called pseudoresistance, which may be due to nonadherence to therapy, poor BP measurement technique, white coat HTN, and submaximal/inappropriate medical management.

o Patients should be queried carefully and often about adherence. Interventions to improve adherence should be carried out, for example, once-a-day regimens, combination pills, reducing cost, and minimizing troublesome side effects.

o Improper BP measurement technique can lead to the false assumption of resistant HTN. Patients should sit quietly for several minutes after arrival before taking the BP and the proper size cuff must always be used. The physician is encouraged to confirm the BP measurements.

o Twenty-four–hour ABPM or patient self-measurement may be necessary to determine which patients have white coat HTN (see the “Ambulatory Blood Pressure Monitoring” section). It is reasonable to suspect white coat HTN in patients who report symptoms of orthostasis and those with no evidence of common comorbidities or end-organ damage.

· Potentially modifiable factors that contribute to resistant HTN include obesity, high sodium intake, excess alcohol consumption, physical inactivity, and other drugs (e.g., NSAIDs, oral contraceptives, sympathomimetic compounds, glucocorticoids, cyclosporine, erythropoietin, and some herbal compounds). Lifestyle interventions to reduce weight, sodium, and alcohol and to increase activity should be strongly encouraged (see the “Other Nonpharmacologic Therapy” section).^98–100

· Secondary causes of HTN (Table 6-3) are more common in patients with resistant HTN, particularly OSA, renal parenchymal disease, primary hyperaldosteronism, and renovascular disease. Screening should be based on clinical suspicion. These conditions are discussed in the “Secondary Hypertension” section.

· Volume (and sodium) expansion is generally considered to be an important contributing factor in most patients with resistant HTN. Diuretic therapy should be maximized (along with sodium intake restriction) and CTDN is the preferred agent rather than HCTZ.⁸¹ In those with a eGFR <30 to 50 mL/minute/1.73 m², a loop diuretic is necessary—furosemide will need to be dosed at least bid.

· The preferred three-drug regimen is an ACE inhibitor (or ARB) plus a long-acting dihydropyridine CCB plus CTDN, all at maximal doses. β-Blockers should be used when there are specific indications.

· When a three-drug regimen (that includes a diuretic) does not achieve goal BP levels, a mineralocorticoid receptor antagonist is often recommended as the fourth agent. Data suggest that both spironolactone (12.5 to 50 mg daily) and eplerenone (50 mg daily to bid) can result in significant BP lowering in patients with resistant HTN without primary hyperaldosteronism and regardless of aldosterone level.^101–104 Patients should be monitored for hyperkalemia, particularly those with CKD and DM. Spironolactone, but not the more selective eplerenone, is also associated with gynecomastia and breast pain.

· When additional treatment is necessary, β-blockers, clonidine, hydralazine, and minoxidil are all potential options, but there are no randomized clinical trials to help determine which of these would be best and in what population of patients.

· When β-blockers are used, one of the newer vasodilating agents (i.e., labetalol, carvedilol, or nebivolol) may be preferable possibly due to greater BP lowering and more favorable metabolic effects compared to typical β-blockers.^105,106 There are no long-term outcome trials of vasodilating β-blockers used solely for the treatment of HTN. Also refer to the “Specific Drug Classes” section.

· The use of clonidine, hydralazine, and minoxidil in resistant HTN is largely empirical; all can lower BP but controlled trials demonstrating improved CV outcomes are lacking. Also refer to the “Specific Drug Classes” section.

· Combining two agents that inhibit the RAS (e.g., ACE inhibitor plus ARB or aliskiren) is not recommended due to the lack of improved outcomes and the possibility of more side effects.^66,67,89,90

· Referral to a hypertension specialist is recommended, if BP cannot be controlled after 6 months of treatment or for specific secondary etiologies that may require assistance with diagnosis and treatment.⁹⁸

Secondary Hypertension

· The large majority of patients who are hypertensive have primary HTN. Occasionally, secondary causes are identified, some of which can be cured and others specifically treated. It is possible to have secondary HTN on top of primary HTN.

· Generally speaking secondary HTN should be at least considered in the following situations:

o Resistant HTN

o Severe HTN in younger patients, particularly those with end-organ damage

o Sudden elevations in previously controlled HTN and those who have experienced a hypertensive emergency (see the “Hypertensive Urgencies and Emergencies” section)

o Persistent, otherwise unexplained, hypokalemia

· The more specific symptoms and signs of various causes of secondary HTN are presented in Table 6-3.

Obstructive Sleep Apnea

· OSA is a fairly common contributor to secondary HTN.^107,108

· Risk factors for OSA include obesity, enlarged tonsils, macroglossia, and craniofacial abnormalities. Use of sedatives, narcotics, or alcohol can also increase the risk for OSA.

· Common complaints for patients with OSA include daytime sleepiness (including falling asleep with driving), not feeling refreshed upon awakening, awakening snorting or gasping, and poor concentration. Patients may report headaches upon awakening. The patient’s bed partner may report witnessing apneic events. In addition, the bed partner may report disruption of their sleep due to the patient’s loud snoring.

· The diagnosis is made by polysomnography with an apnea-hypopnea index >5. An index >30 is consistent with severe OSA. More severe OSA is more associated with HTN.

· Use of continuous positive airway pressure (CPAP) is associated with a reduction in BP but it is relatively modest, about −2/2 daytime and −4/2 nighttime.¹⁰⁹ Even this small reduction can be meaningful with regard to reducing CV events.

Renal Parenchymal Disease

· HTN is a major contributor to the development of CKD, but impaired renal function can also elevate BP resulting in a vicious cycle.

· Approximately 80% of patients with CKD have HTN characterized by a combination of sodium retention, activation of the RAS, enhanced sympathetic activity, and impaired endothelium-mediated vasodilation.

· Treatment should stress sodium restriction, use of diuretics, and the use of ACE inhibitors to reduce proteinuria and intraglomerular pressure.

Renovascular Disease

· Renal artery stenosis is an important correctable cause of HTN responsible for up to 10% of patients with severe HTN resistant to multiple medications. It can result from either fibromuscular disease (more common in the young and in women) or atheromatous disease (more common in the elderly with other CV risk factors).

· Critical stenosis of the renal artery leads to increased renin release from the ischemic kidney, which causes both volume expansion and increased PVR.

· Bilateral disease may present as a sudden decline in renal function after use of an ACE inhibitor or ARB. These agents should be avoided if bilateral disease is known.

· Fibromuscular dysplasia should be considered in young patients without family history.

· Commonly evaluated with duplex ultrasonography, magnetic resonance angiography, or computed tomography angiography.

· Angioplasty is typically done for fibromuscular disease. The choice of treatment for atherosclerotic disease can be quite challenging; both angioplasty with stenting and surgical revascularization are possible. Some patients will have an excellent BP response, some will have minimal effect, and others will have deterioration of renal function. Unilateral disease is more likely to benefit from revascularization.

· Medical treatment to control BP is indicated in all patients and ACE inhibitors or ARBs should be used if tolerated and the patient carefully monitored.

Primary Hyperaldosteronism

· Primary hyperaldosteronism is usually caused by a unilateral adrenal adenoma or bilateral adrenal hyperplasia, rarely adrenocortical carcinoma and familial syndromes.

· It can be difficult to distinguish based on clinical symptoms but should be considered in the presence of unexplained hypokalemia and metabolic alkalosis, especially if the patient is also on an ACE or ARB. However, about half of patients do not have hypokalemia.

· The initial screening test in appropriate patients is the plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio. PAC is high and the PRA is very low, increasing the ratio. If the ratio is <20, the diagnosis of primary hyperaldosteronism is excluded, whereas a ratio of >50 makes the diagnosis very likely. Confirmation is a salt suppression test (oral salt load ×3 days, followed by measurement of 24-hour urinary aldosterone). All drugs that interfere with the renin-angiotensin-aldosterone axis should be discontinued. Inappropriately high aldosterone excretion (>12 μg/day) with Na >200 mEq/day confirms the diagnosis.

· CT or MRI of the adrenal glands can help distinguish between the subtypes when the disease is confirmed. Adrenal vein sampling is sometimes necessary to determine laterality.

· Treatment includes surgical resection of a single adenoma or mineralocorticoid antagonists.

Pregnancy

· A complete discussion of HTN in pregnancy is beyond this scope of this book and will not be undertaken. Most of these patients will be cared for by an obstetrician or a maternal-fetal medicine subspecialist.

· Pregnancy-associated HTN may be preexisting primary HTN. Gestational HTN is defined as new onset BP ≥140/90 developing after 20 weeks’ gestation. Preeclampsia is diagnosed when patients also have proteinuria or certain end-organ damage (e.g., thrombocytopenia, elevated creatinine, pulmonary edema, cerebral or visual symptoms, elevated transaminases). Preeclampsia may be superimposed on chronic primary HTN. Eclampsia is only diagnosed when a seizure has occurred. Severe gestational HTN is defined as BP ≥160/110.¹¹⁰

· The decision to treat HTN in pregnancy must be individualized and is based on multiple factors, including maternal condition, degree of BP elevation, the presence of end-organ damage, and fetal viability.

· Mild to moderate gestational HTN is generally followed carefully without medications.¹¹⁰ Those with severe gestational HTN (≥160/110) may be treated with medications and are usually delivered preterm.

· Management of preeclampsia is more complex and may involve medical management and/or early delivery, sometimes before viability in those with severe preeclampsia.

· Methyldopa has proven safety and modest effectiveness. Other common and safe options include labetalol and long-acting nifedipine. Hydralazine is often used in the acute setting.

· ACE inhibitors and ARBs are contraindicated in pregnancy.

Hypertensive Urgencies and Emergencies

· Hypertensive urgency, also known as severe asymptomatic HTN, is BP usually ≥180/110 mm Hg and the absence of end-organ damage. There is, in fact, no absolute BP level above which an urgency can be declared for all patients. Patients with chronic severe elevations are a fairly low acute risk for poor outcomes. More rapid elevations are associated with increased risk.⁷

· Hypertensive emergency (crisis) is usually associated with a BP ≥180/120 mm Hg and is typified by the presence of end-organ damage (e.g., retinopathy, encephalopathy, cerebral hemorrhage, myocardial ischemia, HF, AKI, aortic dissection, microangiopathic hemolytic anemia, and preeclampsia).⁷

· Hypertensive encephalopathy signifies a loss of cerebrovascular autoregulation and the resultant neurologic manifestations (e.g., delirium, headache, visual disturbance, and seizures).

· The historic term malignant HTN referred to patients with papilledema, retinal exudates, and hemorrhages, and variable renal involvement, who, at the time, had a very poor prognosis because of the lack of effective treatments.

· Hypertensive urgencies and emergencies are usually due to primary HTN, but may be related to secondary causes of HTN, drugs, pregnancy, and central nervous system disorders (e.g., head trauma). Medication nonadherence may be an important contributing factor in some patients.

· When evaluating patients with new (or apparently new) severe BP elevations, the physician should recheck the BP using the best possible technique. Repeating again after the patient has simply rested quietly for approximately a half hour can result in a significant decrease in BP to below a severe level.

· Patients should be carefully questioned about medications, adherence, use of drugs and/or elicit substances, and CV, pulmonary, neurologic, and renal symptoms. These areas should be examined and a funduscopic exam performed. The history and physical may rapidly uncover evidence of end-organ damage and in others laboratory testing may be necessary (e.g., renal function, urinalysis, ECG, CXR).

· Hypertensive emergencies should be managed in the emergency department or in-patient setting. Relatively prompt but modest reductions in BP (e.g., no more than 10% to 20% in the first hour) are indicated and can be achieved with various medications, including labetalol, nitroprusside, nitroglycerine, hydralazine, and fenoldopam. Management needs to individualized based on the nature of the emergency. The management of HTN in acute stroke is very briefly discussed above in the “Specific Patient Populations” section.

· Hypertensive urgencies are sometimes managed in the out-patient setting. Rapid BP lowering is generally not indicated. Patients on chronic antihypertensive therapy who have been nonadherent may be instructed to resume their medications. If the patient is felt to be at increased risk for acute complications due to the BP elevation, relatively fast-acting oral medications may be given to lower BP over a few hours. A reasonable short-term goal is approximately BP ≤160/100 mm Hg; however, there is no controlled trial data to support this or any other specific goal BP. What is clear is that rapid reductions to a normal BP are unnecessary and can result in myocardial and cerebral ischemia.

· Possible oral agents for reducing BP over a few hours include:⁷

o Clonidine 0.1 to 0.2 mg PO.

o Captopril 6.25 to 12.5 mg PO.

o Labetalol 100 to 200 mg PO.

o All can be repeated if necessary.

o Short-acting CCBs, particularly sublingual nifedipine, should not be used in typical medical patients due to the risk of sudden drops in BP, reflex tachycardia, and myocardial ischemia.

· Patients with hypertensive urgency should be followed closely and started on an oral regimen appropriate for long-term management. If the patient has been nonadherent to a previously effective regimen, it should be resumed. If the patient is currently taking a regimen then it should be adjusted (e.g., doses maximized or additional agents added). And if the patient has not been previously prescribed antihypertensive treatment then medication should be started and it may be reasonable to start two medications.

REFERENCES

1.Lewington S, Clarke R, Qizilibash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet2002;360:1903–1913.

2.Centers for Disease Control and Prevention (CDC). Vital signs: awareness and treatment of uncontrolled hypertension among adults—United States, 2003–2010. MMWR Morb Mortal Wkly Rep2012;61:703–709.

3.Chobanian AV, Bakris GL, Black HR, et al. National High Blood Pressure Education Program Coordinating Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA2003;289: 2560–2572.

4.James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA2014;311:507–520.

5.Julius S, Nesbitt SD, Egan BM, et al.; Trial of Preventing Hypertension Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354:1685–1697.

6.Wolff T, Miller T. Evidence for the reaffirmation of the U.S. Preventive Services Task Force recommendation on screening for high blood pressure. Ann Intern Med 2007;147:787–791.

7.U.S. Department of Health and Human Services. National Institutes of Health. Nation Heart Lung, and Blood Institute. Complete Report. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH Publication No. 04–5230. Available at: http://www.nhlbi.nih.gov/health-pro/guidelines/current/hypertension-jnc-7/complete-report.htm. Last accessed 1/21/15.

8.Reeves RA. The rational clinical examinations. Does this patient have hypertension? How to measure blood pressure. JAMA 1995;273:1211–1218.

9.Dolan E, Stanton A, Hisjs L, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension 2005;46:156–161.

10.Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an updated meta analysis. Am J Hypertens2011;24:52–58.

11.Pickering TG, Shimbo D, Haas D. Ambulatory blood pressure monitoring. N Engl J Med 2006;354:2368–2374.

12.Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension versus true normotension: a meta-analysis. J Hypertens 2007;25:2193–2198.

13.Boggia J, Li Y, Thijs L, et al. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 2007;370:1219–1229.

14.Fan HQ, Li Y, Thijs L, et al. Prognostic value of isolated nocturnal hypertension on ambulatory measurement in 8711 individuals from 10 populations. J Hypertens 2010;28:2036–2045.

15.Pickering TG, Miller NH, Ogedegbe G, et al. Call to action on use and reimbursement for home blood pressure monitoring: executive summary. Hypertension 2008;52:1–9.

16.Gerstein HC, Mann JF, Zinman B, et al.; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001;286:421–426.

17.Hillege HL, Fidler V, Diercks GF, et al.; Prevention of Renal and Vascular End Stage Diseased (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 2002;106:1777–1782.

18.Wachtell K, Ibsen H, Olsen MH, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE Study. Ann Intern Med 2003;139:901–906.

19.Elmer PJ, Obarzanek E, Vollmer WM, et al. Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial. Ann Intern Med 2006;144:485–495.

20.Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk. Circulation 2014;129:S76–S99.

21.SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA1991;265: 3255–3264.

22.Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757–764.

23.Perry HM Jr, Davis BR, Price TR, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). JAMA2000;284:465–471.

24.Beckett NS, Peters R, Fletcher AE, et al.; for the HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887–1898.

25.Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ2008;336:1121–1123.

26.Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665.

27.The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–2997.

28.Flack JM, Sica DA, Bakris G, et al. Management of high blood pressure in blacks: an update of the International Society on Hypertension in Blacks consensus statement. Hypertension 2010;56:780–800.

29.Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–1553.

30.Wiysonge CS, Bradley HA, Volmink J, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2012;(11):CD002003.

31.Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.

32.Materson BJ, Reda DJ, Preston RA, et al. Response to a second single antihypertensive agent used as monotherapy for hypertension after failure of the initial drug. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med 1995;155:1757–1762.

33.Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med 1993;328:914–921.

34.Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study. Final results Treatment of Mild Hypertension Study Research Group. JAMA 1993;270:713–724.

35.American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37:S14–S80.

36.UKPDS 39. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ1998;317:713–720.

37.Lewis EJ, Hunsicker LG, Bain RP, et al.; The Collaborative Study Group. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456–1462.

38.Laffel LM, McGill JB, Gans DJ; North American Microalbuminuria Study Group. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. Am J Med 1995;99:497–504.

39.Lewis EJ, Hunsicker LG, Clarke WR, et al.; for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med2001;345:851–860.

40.Brenner BM, Cooper ME, de Zeeuw D, et al.; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med2001;345:861–869.

41.Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes. Circulation 2014;130:e344–e426.

42.O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. Circulation 2013;127: e362–e425.

43.Freemantle N, Cleland J, Young P, et al. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730–1737.

44.The Capricorn Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001;357:1385–1390.

45.Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators. N Engl J Med 1992;327:669–677.

46.The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet1993;342:821–828.

47.Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670–1676.

48.Pfeffer MA, McMurray JJ, Velazquez EF, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–1906.

49.The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA Study). Lancet 2003;362:782–788.

50.V-HeFT II, Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med1986;314:1547–1552.

51.The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.

52.CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765–1773.

53.MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007.

54.Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–1658.

55.Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study (RALES) Investigators. N Engl J Med 1999;341:709–717.

56.Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. The Valsartan Heart Failure Trial Investigators. N Engl J Med 2001;345:1667–1675.

57.Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–776.

58.Zannad F, McMurray JJ, Krum H, et al.; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21.

59.McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–771.

60.Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med 2007;167:1930–1936.

61.Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl2012;2:337–414.

62.Taler SJ, Agrawal R, Bakris GL, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis 2013;62:201–213.

63.Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 1997;349:1857–1863.

64.Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA2002;288:2421–2431.

65.Fink AH, Ishani A, Taylor BC, et al. Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 2012;156:570–581.

66.Mann JF, Schmieder RE, McQueen M, et al.; ONTARGET Investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547–553.

67.Yusuf S, Teo KK, Pogue J, et al.; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–1559.

68.Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke. Stroke 2013;44:870–947.

69.Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke 2010;41:2108–2129.

70.Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage. Stroke 2012;43:1711–1737.

71.Arima H, Chalmers J. PROGRESS: prevention of recurrent stroke. J Clin Hypertens (Greenwich) 2001;13:693–702.

72.Liu L, Wang Z, Gong L, et al. Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature. Hypertens Res 2009;32:1032–1040.

73.Kernan WN, Ovbiagele B, Black HR. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2014;45:2160–2236.

74.PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet2001;358:1033–1041.

75.Yusuf S, Diener HC, Sacco RL, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225–1237.

76.Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med2001;344:3–10.

77.He FJ, Li J, Macgregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013;346:f1325.

78.Jamerson K, Weber MA, Bakris GL, et al.; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–2428.

79.MRC Working Party; Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992;304:405–412.

80.Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly. Circulation 2011;123:2434–2506.

81.Roush GC, Holford TR, Guddati AK. Chlorthalidone compared with hydrochlorothiazide in reducing cardiovascular events: systematic review and network meta-analyses. Hypertension 2012;59:1110–1117.

82.Dhalla IA, Gomes T, Yao Z, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study. Ann Intern Med 2013;158:447–455.

83.Pitt B, Remme W, Zannad F, et al.; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321.

84.Yusuf S, Sleight P, Pogue J, et al.; Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145–153.

85.Pepine C, Handberg E, Cooper-DeHoff R, et al.; INVEST Investigators. A calcium antagonist vs a noncalcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003;290:2805–2816.

86.Grandman AH, Schmieder RE, Lins RL, et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation2005;111:1012–1018.

87.Schmieder RE, Philipp T, Guerediaga J, et al. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Circulation 2009;119:417–425.

88.Brown MJ, McInnes GT, Papst CC, et al. Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet2011;377:312–320.

89.Parving HH, Persson F, Lewsi JB, et al.; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358:2433–2446.

90.Parving HH, Brenner BM, McMurray JJ, et al.; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367:2204–2213.

91.Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303–310.

92.Taylor AL, Ziesche S, Yancy C, et al.; A-HeFT Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049–2057.

93.Horvath K, Jeitler K, Siering U, et al. Long-term effects of weight-reducing interventions in hypertensive patients: systematic review and meta-analysis. Arch Intern Med 2008;168:571–580.

94.Aucott L, Rothnie H, McIntyre L, et al. Long-term weight loss from lifestyle intervention benefits blood pressure?: a systematic review. Hypertension 2009;54:756–762.

95.Siebenhofer A, Jeitler K, Berghold A, et al. Long-term effects of weight-reducing diets in hypertensive patients. Cochrane Database Syst Rev 2011;(9):CD008274.

96.Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation 2014;129:S102–S138.

97.Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997;336:1117–1124.

98.Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A Scientific Statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 2008;117:e510–e526.

99.Vongpatanasin W. Resistant hypertension: a review of diagnosis and management. JAMA 2014;311:2216–2224.

100.Myat A, Redwood SR, Qureshi AC, et al. Resistant hypertension. BMJ 2012;345: e7473.

101.White WB, Carr AA, Krause S, et al. Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. Am J Cardiol2003;92:38–42.

102.Chapman N, Dobson J, Wilson S, et al.; ASCOT Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49:839–845.

103.Václavík J, Sedlák R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial Hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension2011;57:1069–1075.

104.Oxlund CS, Henriksen JE, Tarnow L, et al. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens2013;31:2094–2102.

105.Gress TW, Nieto FJ, Shahar E, et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000;342:905–912.

106.Bakris GL, Fonseca V, Katholi RE, et al.; GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 2004;292:2227–2236.

107.Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 2000;283:1829–1836.

108.Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA 2012;307:2169–2176.

109.Fava C, Dorigoni S, Dalle Vedove F, et al. Effect of CPAP on blood pressure in patients with OSA/hypopnea a systematic review and meta-analysis. Chest 2014;145:762–771.

110.American College of Obstetricians and Gynecologists. Task force on hypertension in pregnancy. Hypertension in pregnancy. Obstet Gynecol 2013;122:1122–1131.