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Published: May 2013

Hypertension

Mohammed A. Rafey

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Definition and Etiology

Normal or optimal blood pressure (BP) is defined as the level above which minimal vascular damage occurs. There is a continuous, consistent, and independent relationship between elevated BP and risk of cardiovascular events. This was clearly demonstrated in a meta-analysis that included 1,000,000 individuals with no history of vascular disease. Among this group, during 12.7 million person-years at risk, there were about 56000 deaths categorized as vascular in origin (12000 stroke, 34000 ischemic heart disease, and 10000 “other vascular”) and 66000 other deaths at ages 40-89 years.1 Results from this study demonstrated that a BP level lower than 115/75 mmHg appears to better define optimal BP.1 According to the Joint National Committee 7 (JNC 7), hypertension is defined as physician office systolic BP level of ≥140mmHg and diastolic BP of ≥90mmHg. The JNC 7 defines normal BP as a systolic BP <120mmHg and diastolic BP <80mmHg. The gray area between systolic BP of 120-139 mmHg and diastolic BP of 80-89 mmHg is defined as “prehypertension.”2

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Prevalence and Risk Factors

One in 3 Americans over the age of 18 years suffers from hypertension. The prevalence is higher among older individuals, women and non-Hispanic blacks. Despite the increase in prevalence, recent data from the National Health and Nutrition Examination Survey (NHANES) demonstrate an improvement in blood pressure control (50%) among Americans with hypertension.3 However, the blood pressure control rate remains suboptimal in people who have serious comorbid conditions such as chronic kidney disease. In a survey of patients with chronic kidney disease, BP control was found to be just 13.2%.4 On a global level, hypertension is a greater problem, with 13.5% of all deaths attributed to BP-related diseases. Individuals in lower economic strata are disproportionately afflicted with hypertension.5

The prevalence of hypertension increases progressively with age. Results from the Framingham study demonstrate that among middle-aged and elderly persons, the residual lifetime risk of developing hypertension is 90%.6 In the majority of patients (95%), hypertension is primary or idiopathic; there is no identifiable risk factor. The remainder of these patients have hypertension caused by renovascular disease, primary aldosteronism, etc.

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Pathophysiology and Natural History

The role of altered salt excretion by the kidney as a central mechanism in the development of hypertension was proposed by Arthur C. Guyton.7 According to Dr. Guyton's hypothesis, there is impaired excretion of sodium ions by tubular epithelial cells in the kidney. To maintain salt and water homoeostasis, the body adopts a pressure-natriuresis approach that ultimately leads to an elevation in BP. Animal studies and studies evaluating Mendelian forms of syndromes that manifest as hypertension and hypotension, such as Bartter's syndrome and Liddle's syndrome, have provided insight into the pathophysiology of hypertension.8 These data confirm that the basic problem in conditions leading to alteration in BP lies in the genetic alteration of sodium transport in renal epithelial cells. Several factors including aging, sympathetic overactivity, toxins, and a low nephron number have been proposed as factors that could ultimately damage the renal tubules and alter epithelial cells, resulting in defective sodium excretion.

In addition, several new conditions that can cause hypertension have been identified. The metabolic syndrome, with insulin resistance and elevation in insulin levels, leads to increased sympathetic activity and hypertension. In patients with obstructive sleep apnea, activation of the sympathetic and renin angiotensin systems has been defined as a possible mechanism for elevation in BP.

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Diagnosis

A detailed history and physical examination is essential for identifying risk factors and stratifying patients to target those who need more aggressive therapy to achieve goal BP. The history should include details of dietary salt intake and should explore lifestyle patterns and social and psychosocial stressors that could potentially affect BP levels. Ophthalmologic assessment and funduscopic examination are simple techniques to identify the severity of disease and target organ damage by grading retinal changes.

Office Blood Pressure Measurement

Careful measurement of BP should be an integral part of any physical examination in a physician's office. Because inaccuracies in blood pressure measurement can occur frequently in clinical practice, the following guidelines should be followed when measuring a patient's BP.9 The patient should be seated comfortably with the back supported and the upper arm bared without constrictive clothing. The legs should not be crossed. The arm should be supported at the level of the heart, and the bladder of the BP cuff should encircle at least 80% of the arm circumference. The blood pressure measuring device should be deflated at the rate of 2 to 3 mm/sec, and the first and last audible sounds should be taken as the systolic and diastolic pressure respectively. Neither the patient nor the observer should talk during the measurement.

Ambulatory Blood Pressure Monitoring

In addition to office BP measurements, 24-hour ambulatory BP monitoring and home BP monitoring are now acceptable methods for evaluating BP more comprehensively on an individual basis. A mean (average) 24 hour BP of ≥130/80 mmHg is regarded as elevated blood pressure.9

The recently released National Institute of Health and Clinical Excellence (NICE) guidelines published in the United Kingdom recommend that a diagnosis of primary hypertension should be confirmed with 24-hour ambulatory blood pressure monitoring or home blood pressure monitoring rather than by relying solely on office blood pressure measurement. Twenty-four-hour ambulatory BP monitoring is indicated to rule out white-coat hypertension, to uncover apparent drug resistance (office resistance), to better define resistant hypertension, to identify hypotensive symptoms while the patient is being treated with anti-hypertensive medications, to monitor episodic hypertension, and to identify autonomic dysfunction states. Twenty-four-hour ambulatory BP monitoring also helps identify abnormal patterns in blood pressure that could remain undetected if a patient is evaluated based on physician office blood pressure measurements alone.

Patterns of Blood Pressure

Based on 24-hour ambulatory BP monitoring and office BP readings, 4 patterns of BP have been described (Figure 1).

In sustained hypertension, BP measurements taken in the office and at home are elevated. Studies done in patients with sustained hypertension for more than 40 years have consistently demonstrated that this condition is closely related to target organ damage and worse cardiac and renal outcomes.

Masked hypertension is defined as normal office BP and elevated home BP.10 Its prevalence ranges from 8% in the general population to as much as 20% in hypertensive patients receiving treatment. Although there are no outcome trials available in patients with masked hypertension, the fact that elevated ambulatory BP is closely related to cardiovascular events implies that its risk profile is similar to that of sustained hypertension. In fact, patients with masked hypertension might have a worse outcome because they are not easily identified and do not receive adequate therapy.

Patients with white coat hypertension have an elevated office BP and normal home BP measurements. The prevalence of white coat hypertension has been reported to be 12% to 18% in the general population. Initially, this was thought to be a benign condition, because prospective trials evaluating white coat hypertension have shown less target-organ damage (increased left ventricular mass, carotid media intimal thickness) than that with sustained hypertension. Clinical studies evaluating cardiovascular outcomes have consistently demonstrated a lower morbidity with white coat hypertension, supporting a more benign course. Based on these studies, it has been hypothesized that white coat hypertension represents an intermediate risk state between normotension and sustained hypertension. One study that followed patients with white coat hypertension demonstrated a significantly elevated risk of stroke in these patients after 6 years of follow-up, emphasizing the importance of long-term follow-up for these individuals.11

Normally, there is a diurnal variation in BP, with a 10% to 20% decrease in systolic BP during sleep, which is described as the normal dipping pattern. Abnormalities in the normal nocturnal dipping pattern of BP have been associated with worse cardiovascular outcomes, even in subjects who are normotensive.12 A 24-hour ambulatory BP measurement remains the only technique to assess the dipping status of patients. Nocturnal hypertension defines a pattern of BP where BP measured during sleep is higher than that measured when the patient is awake. In the African American Study of Kidney Disease and Hypertension (AASK), an abnormal dipping pattern was detected in 80% of patients and nocturnal hypertension was found in 40%.13 All of these patients with an abnormal dipping pattern and nocturnal hypertension had hypertension that was apparently well controlled based on office BP readings.

Home Blood Pressure Monitoring

Several prospective trials have demonstrated that home BP is a better predictor of cardiovascular morbidity and mortality than are office BP measurements. Based on these data, the first home BP monitoring guidelines endorsed by national societies, including the American Heart Association (AHA) and American Society of Hypertension (ASH), among others, have been published.14

These home BP measurement guidelines recommend that a validated device be used to measure BP at home. Blood pressure measurements using such validated devices should be taken before an office visit, with at least 2 morning and 2 evening readings everyday for 1 week (but discarding the readings of the first day), which gives a total of 12 BP readings over a week, based on which clinical decisions can be made. Hypertension is defined as a mean home blood pressure of ≥135/85 mmHg. Home blood pressure monitoring provides an inexpensive alternative to 24-hour ambulatory BP monitoring which is not yet widely available. One of the main drawbacks in home blood pressure measurement when compared to 24-hour ambulatory BP monitoring, is that sleep time blood pressures cannot be recorded and therefore those patients with abnormal dipping pattern in blood pressure and nocturnal hypertension will be missed.

Central Blood Pressure Measurement

Measures of arterial stiffness such as central (aortic) blood pressure and pulse wave velocity (PWV) can now be measured non-invasively in an outpatient setting. Preliminary data from clinical studies indicate that these measures of arterial stiffness may provide better prognostic indices and therapeutic targets in hypertensive patients.15,16 Interventional trials that can test the potential value of treating to a predefined central blood pressure goal for a given brachial blood pressure will clarify the utility of these measures in the future clinical management of hypertension. Guidelines of the European Society of Hypertension have incorporated measurement of PWV for risk stratification of patients with hypertension.

Laboratory Tests

Baseline blood tests are recommended by JNC 7 to identify those individuals at risk for hypertensive events (Table 1). In addition, laboratory tests can provide clues to the etiology in those with resistant or secondary hypertension (Table 2).

Table 1. Baseline blood tests recommended by JNC 7
Routine tests
Electrocardiogram
Urinalysis
Blood glucose, and hematocrit
Serum potassium, creatinine, or the corresponding estimated glomerular filtration rate, and calcium
Lipid profile, after 9- to 12-hour fast, that includes high-density and low-density lipoprotein cholesterol, and triglycerides
Optional test
Measurement of urinary albumin excretion or albumin/creatinine ratio

More extensive testing for identifiable causes is not generally indicated unless blood pressure control is not achieved.


Table 2. Laboratory tests and their clues to etiology in patients with resistant or secondary hypertension
Laboratory Test Possible Clinical Implication Change in Management
Urinalysis Renal disease Lower blood pressure goal
Serum potassium Primary aldosteronism, Cushing syndrome Further evaluation for secondary hypertension
Serum creatinine Renal disease and renovascular disease Further evaluation and more aggressive therapy
Hematocrit Polycythemia Further evaluation
Electrocardiogram Left ventricular hypertrophy More aggressive therapy
Fasting lipid profile Elevated risk for cardiovascular events Aggressive lifestyle modifications

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Summary

  • Proper technique of BP measurement should be an integral part of the evaluation and management of hypertension.
  • Home blood pressure recording is now recommended as an inexpensive and accurate method of measuring blood pressure
  • .
  • Patterns of BP based on ambulatory BP monitoring play an important role in altering therapy and outcomes.
  • Laboratory examination helps in stratifying patients who will need more extensive evaluation and aggressive therapy.

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Treatment

Current JNC 7 guidelines are still largely based on threshold levels of BP. In addition, JNC 7 guidelines do recognize and incorporate the importance of increased cardiovascular risk across a broad spectrum of BP values, as well as a high lifetime risk of developing hypertension (Figure 2). The new JNC 8 guidelines are under preparation and are expected to be released soon. The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) 2009 guidelines have embraced the concept of global cardiovascular risk in recommending that patients be classified not only in relation to grades of hypertension but also in terms of total cardiovascular risk, which represents cumulative risk from the coexistence of multiple factors and target organ damage.17 These guidelines stress that the threshold for hypertension and subsequent drug therapy should remain flexible and should be a function of each patient's individual and total cardiovascular risk.

It is clearly recognized that an increasing BP level is associated with a greater risk of heart attack, stroke, and kidney disease. In fact, for persons aged 40 to 70 years, each increment of 20 mmHg in systolic BP or 10 mmHg increase in diastolic BP doubles the risk of cardiovascular disease across the entire range of BP, from 115/75 to 185/115 mmHg. In an effort to highlight this relationship between elevated BP and cardiovascular disease, a revised classification of hypertension has been provided by JNC 7 (Table 3). Blood pressures below 120/80 mmHg are now considered normal, whereas the previous categories of normal and high-normal BP have been combined into the new classification of pre-hypertension (systolic BP 120-139 mmHg, and diastolic BP 80-89 mmHg).

Table 3: Classification of Blood Pressure (BP)
Classification Systolic BP (mmHg) Diastolic BP (mmHg)
Normal <120 And <80
Prehypertension 120-139 Or 80-89
Stage 1 hypertension 140-159 Or 90-99
Stage 2 hypertension ≥160 Or ≥100

BP, blood pressure.
Data from National Heart, Lung, and Blood Institute: www.nhlbi.nih.gov/guidelines/hypertension/ (accessed April 25, 2013).

Based on JNC 7, patients with sustained hypertension are further divided into stage 1 hypertension (systolic BP 140-159 or diastolic BP 90-99 mmHg), stage 2 hypertension (systolic BP ≥160 or diastolic BP ≥100 mmHg), and those with compelling indications that include diabetes, cardiovascular disease, and renal disease. The JNC 7 recommended a blood pressure goal of <140/90 mmHg for patients with hypertension and more intense lowering (a BP target of <130/80 mmHg) in hypertensive patients with diabetes or kidney disease. In recent years however, large clinical trials performed in patients with kidney disease and diabetes have failed to demonstrate clear benefit with intense blood pressure control.

Data from clinical trials published after the release of JNC 7 have provided new information that will likely be addressed in JNC 8. The Hypertension in the Very Elderly Trial (HYVET) trial is the first study that clearly demonstrated the benefits of anti-hypertensive therapy in older patients with hypertension.18 In this study, lowering BP in patients with hypertension (mean age of 84 years) lowered the risk of both stroke and all-cause mortality. In the AASK, there was no benefit associated with intense blood pressure reduction in hypertensive patients with kidney disease.19 Similar results were seen in hypertensive patients with diabetes who were treated to lower-than-conventional blood pressure goals, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial.20

Lifestyle Modification

Educating patients regarding the importance of non-pharmacologic interventions for effective BP control is an important component of reducing cardiovascular risk in the general population. This is particularly true for the pre-hypertensive and hypertensive patient. However, aggressive efforts are needed to ensure optimal adherence to these recommendations.

Lifestyle modifications include limiting alcohol intake, increasing physical activity, and reducing sodium intake to <6 g of sodium chloride daily. Results from the long-term follow-up of the Trials of Hypertension Prevention (TOHP) study demonstrated that patients who were randomly assigned to a low-salt diet (sodium <1800 mg/24 hr) had a 25% risk reduction in cardiovascular events.21

Weight reduction of as little as 10 to 12 pounds in an obese hypertensive patient can have a considerable effect on elevated BP. Appropriate nutritional counseling can encourage a diet with reduced total fat and cholesterol intake, in addition to providing an adequate daily intake of potassium, calcium, and magnesium. The Dietary Approaches to Stop Hypertension (DASH) trial has provided substantial data that a diet rich in fruits, nuts, vegetables, and low-fat dairy products and with an emphasis on fish and chicken rather than red meat lowered BP even without weight reduction and was particularly effective in those who also restricted sodium chloride intake.22 Dietary recommendations must be made on an individualized basis and should be well supported with continued educational and counseling efforts. Cigarette smoking is a recognized accelerator of cardiovascular disease. Smoking cessation should therefore be strongly encouraged for all patients, and education, counseling, and medication should be provided as needed.

Table 4 lists lifestyle modifications for which evidence-based data are available to support BP reductions. The effects of implementing these modifications are both dose dependent and time dependent and could be greater for some patients. Also, a combination of 2 or more lifestyle modifications can help patients achieve even better results. Lifestyle modifications not only reduce BP but also enhance the efficacy of antihypertensive drugs and decrease cardiovascular risk.

Table 4: Lifestyle modifications to manage hypertension.*†2
Modification Recommendation Approximate SBP Reduction Range
Weight reduction Maintain normal body weight (body mass index, 18.4–24.9 kg/m2) 5-20 mmHg;
10-kg weight loss
Adopt DASH eating plan Consume diet rich in fruits, vegetables, low-fat dairy products, with reduced content of saturated and total fats 8-14 mmHg
Dietary sodium reduction Reduce dietary sodium intake to no more than 100 mmol/day (2.4g sodium or 6g sodium chloride) 2-8 mmHg
Physical activity Engage in regular aerobic physical activity (e.g., brisk walking) at least 30 min/day, most days of the week 4-9 mmHg
Moderation of alcohol consumption Most men: limit consumption to no more than two drinks/day‡
Most women and those who weigh less than normal: no more than one drink/day
2-4 mmHg

DASH, Dietary Approaches to Stop Hypertension; SBP, systolic blood pressure

*For overall cardiovascular risk reduction, stop smoking.
The effects of implementing these modifications are dose- and time-dependent and could be more effective for some patients.
1 oz or 30 mL ethanol: 12 oz beer, 5 oz wine, 1.5 oz of 80-proof whiskey.

Medical Treatment

Prehypertension

An estimated 70 million Americans have prehypertension. The Framingham study demonstrates that if prehypertension is left untreated, these patients go on to develop hypertension. Current recommendations center on nonpharmacologic interventions, which include lifestyle modifications such as weight reduction, increased physical activity, and reduced dietary salt intake. Antihypertensive therapy is not indicated in those with prehypertension at this time.

The Trial of Preventing Hypertension (TROPHY) was conducted to explore whether temporary treatment of prehypertension patients with an antihypertensive agent would reduce the future risk of developing hypertension.23 Patients were randomly assigned in a double-blind manner to treatment with candesartan (16 mg daily; n = 391) or matching placebo (n = 381) for a 2-year period, after which all patients were treated with placebo for an additional 2 years. At the 4-year follow-up, hypertension was noted to have developed less frequently in the individuals initially assigned to take candesartan (53.2% vs 63.0%, relative risk [RR], 0.84; P <0.007). The overall relative risk of hypertension in candesartan group was decreased (RR, 0.58; P = 0.001).

Stage 1 and Stage 2 Hypertetension

Based on Antihypertensive and Lipid Lowering to Reduce Heart Attack Trial (ALLHAT) data, JNC 7 recommends diuretics as first-line therapy for the management of stage 1 hypertension and a combination of 2 drugs as an initial therapy in those with stage 2 hypertension, 1 of which should be a diuretic.24

The ALLHAT trial was designed to compare antihypertensive therapy using an ACE inhibitor, a dihydropyridine calcium antagonist, and an alpha-adrenergic blocker with treatment with an oral diuretic, chlorthalidone, as the standard of therapy. The alpha-adrenergic blocker arm of this study was discontinued early in the trial because it was observed that patients receiving an alpha-adrenergic blocker as monotherapy demonstrated twice the risk of congestive heart failure when compared with those treated with an oral diuretic. The diuretic, calcium antagonist, and angiotensin-converting enzyme (ACE) inhibitor groups were continued to an average follow-up of 4.9 years, at which time no differences were noted among groups with regard to the primary outcome (fatal coronary disease or nonfatal myocardial infarction) or all-cause mortality. However, compared with the diuretic (chlorthalidone) group, the calcium antagonist (amlodipine) group had a significantly higher cumulative incidence of heart failure, and the ACE inhibitor (lisinopril) group had significantly higher incidences of heart failure, stroke, and angina pectoris.

Trial-design issues subsequently generated significant debate regarding the ALLHAT results, particularly the magnitude of the differences noted. Nevertheless, it was concluded from this trial that diuretic therapy is as effective as a calcium channel blocker or an ACE inhibitor from the standpoint of the primary outcome of the trial, and diuretic therapy is superior for select subgroup analyses. A critical look at the trial design suggests a more prudent conclusion that diuretics should be part of all antihypertensive regimens unless they are clearly contraindicated. Further, there was concern that diuretics might worsen glucose tolerance and insulin resistance. Recent data demonstrate that the higher incidence of diabetes mellitus related to thiazides does not appear to be responsible for the increase in risk for coronary heart disease.25

In addition to thiazide diuretics, JNC 7 guidelines also recommend ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers, and calcium channel blockers as first-line therapy for hypertension. Based on evidence of improved outcomes, JNC 7 has recommended several medications for compelling indications (Tables 5 and 6). These include beta blockers and aldosterone antagonists in patients with cardiac disease, ACE inhibitors and ARBs in patients with chronic kidney disease, and diuretics and calcium channel blockers in patients with isolated systolic hypertension. A combination of ACE inhibitors and diuretics instead of ACE inhibitors alone is recommended for preventing recurrence of stroke based on findings of Perindopril Protection Against Recurrent Stroke Study (PROGRESS), which showed a 42% stroke reduction in those treated with this combination of therapy.26

Table 5. Classification and management of blood pressure for adults.2
Initial Drug Therapy

BP Classification SBP,* mm Hg DBP,* mm Hg Lifestyle Modifications With Compelling Indications Without Compelling Indications
Normal <120 And <80 Encourage
Prehypertension 120-139 Or 80-89 Yes No antihypertensive drug indicated Drug(s) for compelling indications†
Stage 1 Hypertension 140-159 Or 90-99 Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination Drug(s) for the compelling indications.‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed
Stage 2 Hypertension ≥160 Or ≥100 Yes Two-drug combination for most† (usually thiazide-type diuretic and ACEI or ARB or BB or CCB)

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta blocker; CCB, calcium channel blocker; DBP, diastolic blood pressure, SBP, systolic blood pressure.

*Treatment determined by highest blood pressure category.
†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
‡Treat patients with chronic kidney disease or diabetes to blood pressure goal <130/80 mmHg.


Table 6: Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes
Recommended Drugs Clinical Trial Basis†

Compelling Indication* Diuretic BB ACEI ARB CCB Aldo ANT
Heart failure ACC/AHA heart failure guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES
Postmyocardial infarction ACC/AHA post-MI guideline, BHAT, SAVE, Capricorn, EPHESUS
High coronary disease risk ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
Diabetes NKF-ADA guideline, UKPDS, ALLHat
Chronic kidney disease NKF guideline, captopril trial, RENAAL, IDNT, REIN, AASK
Recurrent stroke prevention PROGRESS

ACEI, angiotensin-converting enzyme inhibitor; Aldo ANT, aldosterone antagonist; ARB, angiotensin receptor blocker; BB, beta blocker; CCB, calcium channel blocker.

*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed in parallel with the BP.
†Conditions for which clinical trials have demonstrated benefit of specific classes of antihypertensive drugs.

Since the release of JNC 7, new information has emerged in the area of anti-hypertensive therapy. Clinical trials like ASCOT and several meta-analyses have demonstrated that a beta-blocker may not be an appropriate first line medication. Based on results of these studies, beta blockers are now generally indicated as first-line anti-hypertensive medications only in those patients who have compelling cardiac indications.27

In the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which included hypertensive adults at high risk for cardiovascular events, patients were randomly assigned to receive the ACE inhibitor benazepril plus either the calcium channel blocker amlodipine or the diuretic hydrochlorothiazide.28 There was significant reduction in morbidity and mortality in patients in the benazepril plus calcium channel blocker group compared to conventional diuretic based therapy.

In the ONTARGET study, treatment of hypertension in patients who were at high risk for cardiovascular disease with a combination of ACE inhibitor and ARB was associated with additional adverse events without additional benefit.29

Data from large intervention trials in hypertension clearly demonstrate that patients enrolled in these trials required an average of more than 2 medications for blood pressure control.19,24 It is also true that about two-thirds of patients with hypertension required more than 1 anti-hypertensive medication for BP control. Fixed-dose combinations of 2-3 classes of antihypertensive medications are now approved for management of hypertension. These combinations offer superior efficacy as each agent in the combination blocks the counter regulatory system activity triggered by the other. In addition, single fixed-dose combination improves adherence to medications and BP control.

Summary
  • Classification of hypertension is based on BP levels as well as comorbidities such as heart disease, diabetes, and renal disease.
  • Lifestyle intervention should be recommended for patients with prehypertension and all stages of hypertension.
  • Compelling indications mandate therapy with specific medications.

Secondary Hypertension

Approximately 5% of patients with hypertension have a secondary etiology that leads to an elevation in blood pressure. In some conditions, hypertension is potentially curable when the underlying cause is treated.

  • Chronic kidney disease (CKD): CKD is the most common cause of secondary hypertension. Impaired renal function can worsen blood pressure control by reducing sodium and water excretion, and leading to volume overload and hypertension. In the Modification of Diet in Renal Disease (MDRD) study, the prevalence of hypertension increased linearly from 65% to 95% as the glomerular filtration rate declined progressively toward end-stage renal disease.30 Both hypertension and CKD are independently associated with increased cardiovascular mortality and the effect is amplified in CKD patients with hypertension.
  • Renovascular disease: New onset of uncontrolled hypertension or acute worsening of previously well-controlled hypertension in an older individual could likely be due to renal artery stenosis as a result of atherosclerotic renal artery disease. In younger women, fibromuscular dysplasia of renal arteries could lead to uncontrolled hypertension. Significant renal artery stenosis leads to hypoperfusion of the kidney that results in activation of the renin-angiotensin-aldosterone system leading to retention of sodium and water and worsening blood pressure control. Patients may also present with acute worsening in renal function, asymmetric kidney size, or flash pulmonary edema; a systolic diastolic bruit may be heard over the epigastrium.
  • Mineralocorticoid-induced hypertension: A history of spontaneous hypokalemia (serum potassium of <3 mEq/L), inappropriate kaliuresis (urine potassium of >30 mEq/24 hour), plasma rennin activity <1 ng/mL/hour and plasma aldosterone >22 ng/dL increases the likelihood of primary aldosteronism in a hypertensive patient. These patients may also complain of muscle cramping and weakness if they develop severe hypokalemia. In Cushing syndrome, prolonged exposure to endogenous or exogenous cortisol leads to elevated blood pressure. In addition, these patients may also present with moon facies, prominent supraclavicular fat pad, buffalo hump, truncal obesity, and purple striae.
  • Pheochromocytoma: These are chromaffin cell tumors that arise in the adrenal medulla or sympathetic ganglia and cause excess production and secretion of catecholamines. Patients may present clinically with wide fluctuations in blood pressure, sustained hypertension, or with abrupt paroxysms of hypertension. Elevations in blood pressure may be associated with palpitations, headache, pallor, tremor and diaphoresis.
  • Coarctation of aorta: These patients present with radiofemoral pulse delay and a relatively weaker pulse in the legs compared to arms. A bruit may be heard on auscultation of the back.

Diagnostic tests and management of these conditions are provided in Table 7.

Table 7: Workup and management of secondary hypertension
Cause of Secondary Hypertension Diagnostic Tests Management
Renovascular disease Renal duplex ultrasonography, CT or MR angiography, renal angiogram. Balloon angioplasty in patients with FMD; medical management with ACE inhibitor or ARB in combination with a diuretic for patients with atherosclerotic renal artery disease.
Primary aldosteronism Plasma aldosterone renin ratio, salt loading test for confirmation, CT scan of adrenal and adrenal vein sampling for localization. In a patient with adrenal hyperplasia or bilateral functional adrenal adenoma, medical therapy with aldosterone antagonist.
In a patient with unilateral functional adenoma, adrenalectomy of the affected adrenal gland.
Cushing syndrome Dexamethasone suppression test, salivary cortisol levels, CT adrenal gland. Treat primary cause for excess cortisol levels.
Pheochromocytoma Plasma metanephrines, 24-hour urinary metanephrines and catecholamines, CT, MRI, metaiodobenzylguanidine scan if CT or MRI are not conclusive. Adrenalectomy of the affected adrenal gland.
Coarctation of aorta Echocardiogram, MR angiography, aortogram. Angioplasty or surgical correction.
Renovascular disease Renal duplex ultrasonography, CT or MR angiography, renal angiogram. Balloon angioplasty in patient with FMD; medical management with ACE inhibitor or ARB in combination with a diuretic for patient with atherosclerotic renal artery disease.

ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker (antagonist); CT, computed tomography; FMD, fibromuscular dysplasia; MR, magnetic resonance; MRI, magnetic resonance imaging.


Summary
  • A careful history and physical examination of patients with hypertension provides important clues that help in the diagnosis of secondary hypertension.
  • Some forms of secondary hypertension are potentially curable when the underlying pathology is treated.

Resistant Hypertension

Resistant hypertension (RH) is defined as blood pressure that remains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes. Ideally, 1 of the 3 agents should be a diuretic and all agents should be prescribed at optimal dose amounts.31

Recent American Heart Association (AHA) guidelines also include patients who are well controlled but require 4 or more medications as having resistant hypertension. Recent data suggest that the incidence rate of resistant hypertension is 2% in patients who were newly diagnosed with hypertension and receiving therapy. Results from NHANES survey reveal that prevalence of resistant hypertension in US adults is nearly 9%. Patients with resistant hypertension are at a significantly higher risk for cardiovascular events compared to those with non-resistant hypertension.

Resistant hypertension can be thus broadly divided into pseudo-resistant hypertension and true resistant hypertension (Table 8).32 Among patients with pseudo-resistant hypertension, sub-optimal anti-hypertensive therapy has been identified as an important cause leading to uncontrolled hypertension. In the ALLHAT study more than 25% of patients remained on sub-optimal therapy during the course of the study, although their blood pressures were elevated and anti-hypertensive therapy was provided free of cost as part of the study. In patients who have uncontrolled hypertension despite being on adequate anti-hypertensive therapy, it is important to confirm the diagnosis with home BP monitoring or 24-hour ambulatory BP measurement. In a Spanish cohort of patients who were defined as having resistant hypertension based on the American Heart Association (AHA) criteria and who underwent 24-hour ambulatory BP measurement, 37.5% patients were found to have white coat hypertension.

Table 8. Causes of Resistant Hypertension
Pseudo-resistant hypertension:
Incorrect technique in measuring blood pressure
Pseudohypertension
Lack of adherence to lifestyle interventions
Foods and over-the-counter medications
Sub-optimal therapy
Lack of patient adherence to antihypertensive therapy
White coat hypertension
True resistant hypertension:
Sleep apnea
Paroxysmal hypertension
Hypertension related to secondary etiology

Pseudo-hypertension can lead to a false positive diagnosis of resistant hypertension. In this condition, the measured cuff pressure is inappropriately higher than true intra-arterial blood pressure due to excessive arteriosclerosis and arterial stiffness which is common in the elderly. The thickened and calcified arteries that result from arteriosclerosis are not compressed adequately during inflation of the blood pressure cuff. There is currently no reliable clinical method to diagnose or detect this condition.

Obstructive sleep apnea (OSA) is increasingly being recognized as an important cause for the development of resistant hypertension. Several studies have reported a strong correlation between obstructive sleep apnea and hypertension.33 Several mechanisms are hypothesized to explain this association, including chronic night time hypoxemia, altered chemoreceptor stimulation, and activation of the sympathetic and renin-angiotensin systems. Frequent night-time hypoxia and hypercapnia also appear to stimulate aldosterone production independent of plasma renin levels.

Management of resistant hypertension includes a detailed history, accurate BP measurement, recommending lower dietary salt intake, and other lifestyle interventions. Food and medications that interfere with hypertension therapy or cause elevation of blood pressure should be discontinued. Antihypertensive therapy should be optimized. The choice and dose of diuretic should be individualized to each patient. There is some evidence from clinical trials suggesting that the addition of an aldosterone antagonist to an existing anti-hypertensive regimen ─ even in those patients with normal or low aldosterone levels ─ improves blood pressure levels. In patients with OSA and resistant hypertension, treatment with aldosterone antagonists and non-invasive positive pressure ventilatory support (NIPPV) may improve blood pressure control. If secondary hypertension is suspected it should be thoroughly investigated, as in some instances, such as pheochromocytoma or adrenal adenoma, this may be of curable etiology.

Two new techniques to treat resistant hypertension that are undergoing clinical trials involve baroreceptor activation therapy and renal artery denervation in order to lower blood pressure:

  • Baroreceptor activation therapy is performed using a Rheos baroreflex hypertension therapy system which is surgically implanted in the subclavicular region. The electrodes connected to this device are attached to the carotid body on each side of the neck. Activation of baroreceptors leads to significant lowering of blood pressure. A phase III trial evaluating this device has yielded mixed results. Although there was sustained long-term reduction in blood pressure, 2 end points (acute systolic BP response and procedural safety) did not meet pre-specified expectations.34
  • The Symplicity renal denervation system uses a catheter to perform radiofrequency ablation when applied to the lumen of renal arteries through a femoral access. In the Symplicity HTN-1 study, 153 patients with resistant hypertension (baseline BP of 176/98 + 17/15 mmHg) underwent catheter-based renal sympathetic denervation. Patients experienced a sustained BP reduction averaging 32/14 mmHg at 24 months; 92% had an office blood pressure reduction of >10mmHg and 97% of patients were free of procedure-related complications.35

These interventions are not yet FDA approved but hold promise to lower blood pressure in patients with resistant hypertension.

Hypertensive Emergencies

Approximately 1% of Americans with hypertension are estimated to be affected by hypertensive crises. Hypertensive crisis broadly covers both hypertensive urgency and emergency. JNC 7 defines hypertensive emergency as severe elevation in BP (>180/120 mmHg) complicated by evidence of impending or progressive target organ dysfunction and damage.2 When severe elevation in BP occurs without acute target organ dysfunction or damage, it is defined as hypertensive urgency.

Hypertensive emergencies are more common in patients with essential hypertension (20%-30% in Caucasians and 80% in African Americans). Factors such as renal failure, heart failure, cerebrovascular accidents, and nonadherence to antihypertensive therapy are associated with hypertensive crisis. Illicit drug use is an important cause for hypertensive crisis. The pathophysiology of hypertensive crisis remains unclear. It has been proposed that an acute increase in humoral factors leads to systemic vasoconstriction and increased vascular resistance causing elevation in blood pressure. Very high BP in turn causes shear stress and endothelial injury thereby further aggravating blood pressure levels and hypertensive crisis.36

Patients with hypertensive emergencies may present with hypertensive encephalopathy, intracerebral hemorrhage, acute myocardial infarction, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting aortic aneurysm, or eclampsia. When evaluating patients with severe hypertension, it is important to distinguish hypertensive urgency from hypertensive emergency as the treatment plan is based on the diagnosis. Patients with hypertensive emergency require immediate BP lowering (by 25%) within minutes to an hour and then gradually to 160/110 mmHg over next 2 to 6 hours in order to prevent or limit target organ damage. Rapid lowering of BP to near normal levels is avoided as it could lead to renal, cerebral and coronary ischemia. These patients require monitoring in intensive care units and parenteral anti-hypertensive medications (Table 9). In contrast, for patients with hypertensive urgency, blood pressure can be lowered gradually over 24-48 hours.

Table 9. Intravenous Agents for Hypertensive Emergencies
Agent Onset Duration Advantages Disadvantages
Nitroprusside Immediate 1-2 minutes Potent, titratable Cyanide, isocyanide
Nitroglycerine 2-5 minutes 3-5 minutes Coronary perfusion Tolerance, variable efficacy
Fenoldopam <5 minutes 5-10 minutes Renal perfusion Increased intraocular pressure
Hydralazine 10-20 minutes 3-8 hours Eclampsia Tachycardia, headache
Nicardipine 5-15 minutes 1-4 hours CNS protection Avoid in CHF and cardiac ischemia
Enalaprilat 15-30 minutes 6 hours CHF, acute LV failure Avoid in MI

CNS, central nervous system; CHF, congestive heart failure; LV, left ventricular; MI, myocardial infarction.


Summary
  • Underlying history of hypertension is an important factor in patients who develop hypertensive crisis.
  • Triaging patients with hypertensive emergencies early and initiating parenteral antihypertensive therapy helps to limit target organ damage.
  • Overly rapid lowering of BP to normal levels in patients with hypertensive emergencies should be avoided as it can cause renal, cerebral, and coronary ischemia.

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Conclusions

Hypertension is an important modifiable risk factor. Although a majority of patients with hypertension remain asymptomatic, a careful early evaluation identifies those with or at risk for target organ damage with left ventricular hypertrophy and microalbuminuria, both of which portend serious future cardiovascular and renal events. Early identification of these patients and achieving BP goals could reverse early end-organ damage and improve outcomes in these patients. Analysis of the data from Framingham Heart study demonstrates that a 2-mmHg reduction in blood pressure would result in 14% reduction in the risk of stroke and transient ischemic attacks, and a 6% reduction in risk of coronary heart disease. The effective management of hypertension is therefore an important primary health care objective in managing cardiovascular and renal disease.

It must be emphasized that accurate measurement of blood pressure is of fundamental importance in management of hypertension. It is also important to identify the modifiable risk factors that can help improve blood pressure control and reduce cardiovascular and renal damage. Certain classes of medications appear to have a more beneficial effect than others in managing high-risk patients with hypertension leading to the recommendation of compelling indications. Thus anti-hypertensive therapy should be tailored and personalized based on an individual's health profile. For instance, in patients with hypertension associated with unusual features such as early onset of severe hypertension or clinical features such as palpitations and diaphoresis, further evaluation for secondary hypertension is recommended as these conditions are potentially curable. On the other hand, patients with severely elevated hypertension and with evidence of target organ dysfunction or damage need to be triaged early and started on parenteral antihypertensive therapy to lower cardiovascular and renal morbidity and mortality.

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