Definition and etiology

Normal or optimal blood pressure (BP) is defined as the level above which minimal vascular damage occurs. The Joint National Committee 7 (JNC 7) defines normal BP as a systolic BP less than 120 mm Hg and diastolic BP less than 80 mm Hg.¹ 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 evaluated mortality due to vascular events in a million participants that included 61 observational trials. Results from this study demonstrated that a BP level of less than 115/75 mm Hg appears to better define optimal BP.²

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Prevalence and risk factors

An estimated 75 million Americans have hypertension, and blood pressure is well controlled to their goal BP level in fewer than one in three.³ The highest prevalence of hypertension is noted in African Americans. Blood pressure control rate is recognised to be suboptimal or even lower in those who have serious comorbid conditions like chronic kidney disease. In a survey of patients with chronic kidney disease, BP control was found to be a dismal 13.2%.⁴ On a global level, hypertension is a greater problem, with 13.5% of all deaths attributed to BP-related diseases. A majority of those who carry this disease burden belong to lower economic strata.⁵

The prevalence of hypertension increases progressively with age. Results from the Framingham study demonstrate that in middle-aged and elderly persons, the residual lifetime risk of developing hypertension is 90%.⁶ Hypertension is primary or idiopathic 95% of the time when there is no identifiable risk factor and is of secondary etiologies like renovascular disease, primary aldosteronism, and others in 5% patients.

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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 Dr Arthur C. Guyton.⁷ According to Guyton's hypothesis, there is impaired excretion of sodium ions by tubular epithelial cells of the kidney. To maintain salt and water hemostasis, the body adapts a pressure-natriuresis approach that ultimately leads to 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 identifiying 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 is a simple technique to identify 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 BP inaccuracies are common in clinical practice, the following guidelines⁹ should be followed when measuring a patient's BP. 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 heart level, and the bladder of the cuff should encircle at least 80% of the arm circumference. The mercury column should be deflated at 2 to 3 mm/sec, and the first and last audible sounds should be taken as systolic and diastolic pressure. The column should be read to the nearest 2 mm Hg. 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. Study data further advocate measurement of arterial stiffness parameters and central BP. In the Conduit Artery Function Evaluation (Café) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which recruited 2073 patients, radial artery applanation tonometry and pulse-wave analysis was used to derive central aortic pressures and hemodynamic indexes on study visits for up to 4 years. In this trial, greater lowering of central BP appeared to improve cardiovascular outcomes, although peripheral BP reduction was similar in all groups.^10-11 Guidelines of the European Society of Hypertension have incorporated measurement of these vascular parameters at those centers where it is available.

Ambulatory blood pressure 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 antihypertensives, to monitor episodic hypertension, and to identify autonomic dysfunction states.

Patterns of Blood Pressure

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

Figure 1: Click to Enlarge

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 events.

Masked hypertension is defined as normal office BP and elevated home BP.¹² 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, these patients 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 BPs. Its prevalence has been reported to be 12% to 18 % the general population. Initially it 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 white coat hypertension patients demonstrated a significantly elevated risk of stroke in these patients after 6 years of follow-up, emphasizing the importance of long-term follow-up in these patients.¹³

Normally, there is a diurinal 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.¹⁴ 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%.¹⁵ 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 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.¹⁶

These home BP measurement guidelines recommend that a validated device be used to measure BP at home. BP measurements using such validated devices should be taken before an office visit, with at least two morning and two evening readings every day for 1 week (but discarding the readings of the first day), which gives a total of 12 BP readings with which clinical decisions can be made.

Laboratory Tests

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

Summary

• Proper technique of BP measurement should be an integral part in evaluation and management of hypertension.
• 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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Figure 2: Click to Enlarge

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 (Fig. 2). The new JNC 8 guidelines are expected to be released in 2009. 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 should be classified not only in relation to grades of hypertension but also in terms of their total cardiovascular risk, which represents cumulative risk from the coexistence of multiple risk 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 mm Hg in systolic BP or 10 mm Hg in diastolic BP actually doubles the risk of cardiovascular disease across the entire range of BP, from 115/75 to 185/115 mm Hg. 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 2). Blood pressures below 120/80 mm Hg are now considered normal, whereas the previous categories of normal and high-normal BP have been combined into the new classification of prehypertension (systolic BP 120-139 mm Hg, and diastolic BP 80-89 mm Hg).

Based on JNC 7, patients with sustained hypertension are further divided into stage 1 hypertension (systolic BP 140-159 or diastolic BP 90-99 mm Hg), stage 2 hypertension (systolic BP =160 or diastolic BP =100 mm Hg), and those with compelling indications that include diabetes, cardiovascular disease, and renal disease.

Lifestyle Modification

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

Lifestyle modifications include limiting alcohol intake, increasing physical activity, and reducing sodium intake to less than 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 randomized to a low-salt diet (sodium <1800 mg/24 hr) had a 25% risk reduction in cardiovascular events.¹⁸

Weight reduction of as little as 10 to 12 pounds in the obese hypertensive patient can have a considerable impact on elevated BP. Appropriate nutritional counselling 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.¹⁹ Dietary recommendations must be made on an individualized basis and should be well supported with continued educational and counselling efforts.

Cigarette smoking is a recognized accelerator of cardiovascular disease. Smoking cessation should therefore be strongly encouraged for all patients, and education, counselling, and medication should be provided as needed.

Table 3 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 two or more lifestyle modifications can achieve even better results. Lifestyle modifications not only reduce BP but also enhance the efficacy of antihypertensive drugs and decrease cardiovascular risk.

Medical Treatment

Prehypertension

An estimated 70 million Americans have prehypertension. The Framingham study demonstrates that if their prehypertension is left untreated, these patients go on to develop hypertension. Current recommendations center around nonpharmacological interventions, which include lifestyle modifications like 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 their future risk of developing hypertension.²⁰ Patients were randomized 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 often in the group initially randomized to 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 two drugs as an initial therapy in those with stage 2 hypertension, one of which should preferably be a diuretic.²¹

The ALLHAT trial was designed to compare antihypertensive therapy using an ACE inhibitor, a dihydropyridine calcium antagonist, and an α-adrenergic blocker with treatment with an oral diuretic, chlorthalidone, as the standard of therapy. The α-adrenergic blocker arm of this study was discontinued early in the trial because it was observed that patients receiving an α-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.

In addition, there was also a concern that diuretics might worsen glucose tolerance and insulin resistance. Recent data demonstrates 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.²²

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. Since the publication of JNC 7 guidelines, studies have shown that beta-blocker therapy might not be effective and in fact might increase the risk of stroke.^23,11 In the newer guidelines published by various national societies, beta blockers have been removed as first-line therapy and are recommended only with a compelling indication in those with cardiac disease.

Based on evidence of improved outcomes, JNC 7 has recommended several medications for compelling indications (Tables 4 and 5). These include beta blockers and aldosterone antagonists in those with cardiac disease, ACE inhibitors and ARBs in those with chronic kidney disease, and diuretics and calcium channel blockers in those 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.²⁴

Further complexity in instituting an antihypertensive combination regimen was introduced by results of the ASCOT, study which showed that a calcium channel blocker and ACE inhibitor combination had a better outcome when compared to a beta blocker and diuretic combination regimen. A better outcome was shown to occur even though there was a similar BP reduction in both treatment arms.

A lower BP goal appears to be a clear winner in most antihypertensive trials to reduce cardiovascular and renal outcomes. Experts in hypertension, however, continue to be perplexed by the fact that certain classes of medications appear to have a more beneficial effect than others. In the Café study, a further reduction of central systolic BP in calcium channel blockers and ACE inhibitors arm appeared to better explain the beneficial outcomes with this combination therapy in the main ASCOT study.¹¹

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Summary

• Classification of hypertension is based on BP levels as well as comorbidities like 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.

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Conclusions

The ultimate public health goal of antihypertensive therapy is to reduce the morbidity and mortality from cardiovascular and renal events. It is well established that lowering BP reduces cardiovascular risk. Numerous clinical trials have also made it clear that treating to achieve lower BP goals can be associated with further risk reduction. A report using data from the National Health and Nutrition Examination Survey (NHANES) Epidemiologic Follow-up Study has estimated the absolute benefit associated with a 12-mm Hg reduction in systolic BP over 10 years. For the patient with stage 1 hypertension (systolic BP 140-159 mm Hg and/or diastolic BP 90-99 mm Hg) and additional cardiovascular risk factors, one death would be prevented for every 11 patients treated. In the presence of cardiovascular disease with target organ damage, only nine patients would require BP reduction to prevent a death. Because most persons with hypertension, particularly those older than 50 years, reach their diastolic BP goal once systolic BP is at goal, the primary focus in hypertension therapy should be on achieving the systolic BP goal. Evidence exists that treating systolic BP and diastolic BP to a target below 140/90 mm Hg is associated with reduction in cardiovascular disease complications. Data now support treatment to a BP goal below 130/80 mm Hg in patients with hypertension, diabetes mellitus, or renal disease.

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 for left ventricular hypertrophy and microalbuminuria, which portend serious future cardiovascular and renal events. Early identification of these patients and achieving BP goals could potentially reverse early end-organ damage and improve outcomes in these patients. The effective management of hypertension is therefore an important primary health care objective in managing cardiovascular and renal disease.

The disappointing control rates of hypertension can be significantly improved if both health care providers and patients can be encouraged to embrace lower target BPs as suggested by recent results from clinical trials. The majority of patients with uncontrolled hypertension are older adults with isolated stage 1 or 2 systolic hypertension, most of whom have access to and regular visits with their health care providers.

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