Main symptoms and and syndromes in cardiology.
Essential arterial hypertension
Affecting one quarter of the adult population (60 million in the United States and 1 billion people worldwide), arterial hypertension is the leading cause of death in the world and the most common cause for an outpatient visit to a physician; it is the most easily recognized treatable risk factor for stroke, myocardial infarction, heart failure, peripheral vascular disease, aortic dissection, atrial fibrillation, and end-stage kidney disease. Despite this knowledge and unequivocal scientific proof that treatment of hypertension can prevent many of its life-altering complications, hypertension remains untreated or undertreated in the majority of affected individuals in all countries, including those with the most advanced systems of medical care. Inadequate treatment of hypertension is a major factor contributing to some of the adverse secular trends since the early 1990s, including an increased incidence of stroke, heart failure, and kidney failure plus a leveling off of the decline in coronary heart disease mortality.
Across populations, the risks of heart disease and stroke increase continuously and logarithmically with increasing levels of systolic and diastolic blood pressure at or above 115/75 mm Hg . Thus, the dichotomous separation of “normal” from “high” blood pressure is artificial, and the definition of arterial hypertension (i.e., high blood pressure) has been a moving target. On the basis of results of randomized clinical drug trials, hypertension currently is defined as a usual blood pressure of 140/90 mm Hg or higher, the value above which the benefits of treatment appear to outweigh the risks. Prehypertension is a new designation for mildly elevated blood pressures between 120/80 and 139/89 mm Hg, a level at which progression to hypertension is twice as likely as with a blood pressure below 120/80 mm Hg, and cardiovascular risk retains its continuous log-linear function compared with lower blood pressures. The cardiovascular mortality rate is only half as great at 120/80 mm Hg as at 140/90 mm Hg, but it is unknown whether the benefits of treating prehypertension outweigh the risks.
The asymptomatic nature of the condition impedes early detection, which requires regular blood pressure measurement. Because most cases of hypertension cannot be cured, blood pressure control requires lifelong treatment with prescription medication, which is costly and often causes more symptoms than the underlying disease process. Effective management requires continuity of care by a regular and knowledgeable physician as well as sustained active involvement by an educated patient.
Arterial hypertension, defined as a systolic blood pressure (SBP) in excess of
Data from the National Health and Nutrition Examination Survey has demonstrated that if a blood pressure (BP) of 140/90 mm Hg is considered to be normal, only 27% of hypertensive patients are adequately controlled in the
The beating heart generates pressure and flow waves which propagate throughout the arterial system. The shape of the pressure and flow waves is altered by their continuous interaction with the non-uniform arterial system. The pressure and flow waves can be studied in terms of a forward component, running from the heart itself, and a backward component carrying information on the peripheral arterial system.
In the presence of arteriosclerosis and aortic stiffening (consequences of arterial hypertension), the pulse wave velocity is increased, causing the pulse waves to reflect more quickly off the arteriolar vessels and return to the large vessels during systole. This amplifies SBP. In the presence of normal vascular compliance, the reflected waves return during diastole and augment DBP. Consequently, arteriosclerosis tends simultaneously to increase SBP and decrease DBP, resulting in a widened pulse pressure.
A widened pulse pressure increases cardiovascular morbidity because elevated SBP is associated with greater left ventricular workload and myocardial oxygen demand, whereas a decreased DBP may decrease coronary perfusion, resulting in decreased myocardial oxygen supply and a greater risk for myocardial ischemia and injury.
Hypertension (systolic pressure 
140 mm Hg or diastolic pressure 90 mm Hg) is present in one in four adults in the United States.1 The prevalence is higher among blacks and older persons, especially older women. Table 1 shows the classification of blood pressure according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2 Hypertension is a risk factor for stroke, myocardial infarction, renal failure, congestive heart failure, progressive atherosclerosis, and dementia.3 Systolic pressure is a stronger predictor of cardiovascular events than is diastolic pressure,4 and isolated systolic hypertension, which is common among older persons, is particularly hazardous.5 There is a continuous, graded relation between blood pressure and the risk of cardiovascular disease; the level and duration of hypertension and the presence or absence of coexisting cardiovascular risk factors determine the outcome.6 Treatment of hypertension reduces the risk of stroke, coronary artery disease, and congestive heart failure, as well as overall cardiovascular morbidity and mortality from cardiovascular causes. However, only 54 percent of patients with hypertension receive treatment and only 28 percent have adequately controlled blood pressure.1
Strategies and Evidence
Evaluation
Accurate measurement of blood pressure7 and verification of elevated pressure on multiple occasions over time are important. Ambulatory or home blood-pressure monitoring8 can identify “white-coat hypertension” (blood pressure that is elevated when measured during an office visit but that is otherwise normal) and prevent unnecessary treatment. White-coat hypertension, present in 20 percent of patients with elevated blood pressure, is associated with a lower cardiovascular risk than is sustained hypertension, but it may be a precursor of sustained hypertension and therefore warrants monitoring.
In addition to the history taking and physical examination, several tests are routinely indicated in patients with hypertension: urinalysis, complete blood count, blood chemical tests (measurements of potassium, sodium, creatinine, fasting glucose, total cholesterol, and high-density lipoprotein), and 12-lead electrocardiography. The evaluation should identify signs of cardiovascular, cerebrovascular, or peripheral vascular disease and other cardiovascular risk factors that are frequently present in patients with hypertension. Severe or resistant hypertension or clinical or laboratory findings suggesting the presence of renal disease, adrenal hypertension (due to abnormal mineralocorticoid secretion or pheochromocytoma), or renovascular hypertension should be further investigated. Essential, or primary, hypertension, the focus of this article, is the diagnosis in over 90 percent of cases.
Treatment
The primary goal of the treatment of hypertension is to prevent cardiovascular disease and death. Coexisting cardiovascular risk factors increase the risks associated with hypertension and warrant more aggressive treatment. The five-year risk of a major cardiovascular event in a 50-year-old man with a blood pressure of 160/110 mm Hg is 2.5 to 5.0 percent; the risk doubles if the man has a high cholesterol level and triples if he is also a smoker.9
The benefits of lowering blood pressure, first demonstrated after short-term treatment of malignant hypertension,10 have subsequently been demonstrated in all stages of hypertension. Trials involving patients with stage 1 or 2 hypertension showed that lowering systolic pressure by 10 to
Determination of the need for drug therapy is based on a combined assessment of the blood-pressure level and the absolute risk of cardiovascular disease (Figure 1). Patients with stage 1 hypertension can be treated with lifestyle modifications alone for up to one year, if they have no other risk factors, or for up to six months, if they have other risk factors. Drug treatment should be provided if blood pressure remains elevated after a trial of lifestyle modifications alone. Lifestyle modifications and antihypertensive therapy are indicated for patients with cardiovascular or other target-organ disease (renal, cardiac, cerebrovascular, or retinal disease) and for those with stage 2 or 3 hypertension. Patients with diabetes are at high risk, and drug therapy is indicated in such patients even if blood pressure is at the high end of the normal range.
Figure 1. Treatment of Hypertension According to the Level of Blood Pressure and Cardiovascular Risk.
Two or more blood-pressure readings separated by two minutes should be averaged. If the pressure is at the high end of the normal range, it should be rechecked yearly. Stage 1 hypertension should be confirmed within two months. Patients with stage 2 hypertension should be evaluated and referred for care within one month; those with stage 3 hypertension should be evaluated immediately or within one week. If systolic and diastolic values are in different categories, the recommendations for the higher reading should be followed.
Laboratory tests include a complete blood count; measurements of potassium, sodium, creatinine, fasting glucose, total cholesterol, and high-density lipoprotein cholesterol; and urinalysis. ECG denotes electrocardiography. Cardiovascular or other target-organ disease denotes left ventricular hypertrophy, angina or prior myocardial infarction, prior coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy.
For patients with multiple risk factors, clinicians should consider drugs as initial therapy along with lifestyle modifications. Clinically important risk factors include smoking, dyslipidemia, diabetes mellitus, an age of more than 60 years, male sex, postmenopausal status in women, and a family history of cardiovascular disease for women under the age of 65 years and men under the age of 55 years. Adapted from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2
Lifestyle Modifications
Table 2 lists lifestyle modifications recommended for all patients with hypertension. The Dietary Approaches to Stop Hypertension (DASH) study showed that eight weeks of a diet of fruits, vegetables, low-fat dairy products, whole grains, poultry, fish, and nuts, with limited fats, red meat, and sweets, reduced systolic pressure by
Restriction of sodium intake to
Whether lifestyle modifications can be sustained is a concern. Four years after enrollment in the Treatment of Mild Hypertension Study, patients with stage 1 hypertension had gained back half the weight lost after one year of intervention and were less successful at maintaining a low sodium intake and an increased level of physical activity than they had been at one year.20 Nevertheless, lifestyle modifications alone controlled blood pressure at four years in 59 percent of the patients.
Most clinical trials of lifestyle modifications have been underpowered or of insufficient duration to evaluate the effect of these interventions on major cardiovascular outcomes. However, lifestyle modifications should be encouraged, since they are safe and inexpensive and, when combined with drug therapy, may result in better blood pressure control and an improved quality of life.21
Treatment Goal for Blood Pressure
The risk of cardiovascular disease remains higher in treated patients with hypertension than in persons with normal blood pressure, suggesting that treatment targets have not been low enough. Greater reductions in blood pressure have been shown to be safe and beneficial.22,23 In the Hypertension Optimal Treatment trial, the risk of major cardiovascular events was lowest among patients whose blood pressure had been reduced to 138.5/82.6 mm Hg. An additional reduction did not further reduce the risk of events iondiabetic patients, but it was not harmful. Among diabetic patients, the lowest rates of major cardiovascular events and death from cardiovascular causes were achieved with the lowest blood pressure. In patients over the age of 65 years, morbidity and mortality from cardiovascular disease are reduced when systolic pressure is lowered to a level below
Choice of Antihypertensive Drugs
Most antihypertensive drugs reduce blood pressure by 10 to 15 percent. Monotherapy is effective in about 50 percent of unselected patients, and those with stage 2 or 3 hypertension ofteeed more than one drug.25 There have been few comparative trials of antihypertensive agents that have had sufficient power to demonstrate an advantage of one drug over another, and there is individual variation in responsiveness to drugs. Thus, the choice of therapy is based on a combined assessment of several characteristics of the patient: coexisting conditions, age, race or ethnic group, and the response to previously used drugs, including the presence or absence of adverse reactions.
A critical issue is whether a drug reduces cardiovascular morbidity and mortality. As compared with placebo, diuretics and beta-blockers reduce the risk of stroke, coronary heart disease, and overall mortality from cardiovascular disease in unselected patients with hypertension who do not have preexisting coronary disease, diabetes, or proteinuria.11,12 A meta-analysis of trials involving more than 26,000 patients showed that, as compared with placebo, angiotensin-converting–enzyme (ACE) inhibitors reduce the risk of stroke, coronary heart disease, major cardiovascular events, death from cardiovascular causes, and death from any cause,26 although the results were heavily dependent on a trial in which all the participants had preexisting cardiovascular disease or diabetes and some did not have hypertension.27 Calcium-channel antagonists, as compared with placebo, reduce the risk of stroke, major cardiovascular events, and death from cardiovascular causes; however, these drugs do not significantly reduce the risk of coronary heart disease, heart failure, or death from any cause.26
The question of whether antihypertensive agents differ in their ability to prevent adverse outcomes has been difficult to answer.28 Some data suggest potentially important differences. For example, ACE inhibitors were more effective than calcium-channel antagonists in preventing coronary heart disease in one trial,29 but not in another, larger study.30 A meta-analysis of clinical trials suggests that ACE inhibitors are more effective than calcium-channel antagonists in reducing the risk of heart failure but not in reducing the risk of stroke, death from cardiovascular disease, or death from any cause.26 Losartan, an angiotensin-receptor antagonist, has recently been shown to be more effective than atenolol in reducing the risk of stroke.31 Another meta-analysis suggests that calcium-channel antagonists may prevent stroke to a greater extent than diuretics or beta-blockers but have not been shown to provide similar protection against coronary heart disease.32 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the largest randomized trial comparing several antihypertensive agents as initial therapy, demonstrated that in patients older than 55 years (35 percent of whom were black and 19 percent of whom were Hispanic), diuretic-based therapy was as effective as treatment with calcium-channel antagonists or ACE inhibitors in preventing major coronary events.33 Diuretic-based therapy was slightly more effective than treatment with calcium-channel antagonists in preventing heart failure and was more effective than treatment with ACE inhibitors in preventing stroke and heart failure. A smaller study of elderly white men and women with hypertension, showed that ACE-inhibitor–based therapy was slightly more effective than diuretic-based therapy in preventing myocardial infarction (only in men) but not stroke.34
On the basis of the available data, diuretics or beta-blockers remain appropriate for the initial treatment of uncomplicated hypertension, despite the concern that these agents may be associated with adverse metabolic effects (e.g., hyperuricemia and impaired glucose tolerance). Alternative drugs are preferable for patients with certain coexisting medical conditions (Table 3). In particular, ACE inhibitors and angiotensin-receptor antagonists are appropriate initial therapy in patients with diabetes mellitus, renal disease, or congestive heart failure35,36 (though beta-blockers and diuretics are also useful in patients with heart failure); ACE inhibitors can also be used in patients with prior myocardial infarction or coronary artery disease. Short-acting calcium-channel antagonists cause a rapid, acute drop in blood pressure, which may precipitate coronary ischemia, and long-acting calcium-channel antagonists are therefore preferred when this class of agent is chosen.37 Alpha-blockers relieve symptoms associated with prostatic hypertrophy. Since they are not as effective as other agents in reducing the risk of cardiovascular disease, they should be used as second- or third-line therapy.33
Other Considerations in the Choice of Therapy
Age and race have been shown to be determinants of the response to specific antihypertensive medications. The Department of Veterans Affairs Cooperative Study reported that younger whites had a good response to ACE inhibitors and beta-blockers, whereas older blacks had a better response to diuretics or calcium-channel antagonists.25
Hypertension is more severe and target-organ damage, particularly end-stage renal disease, more prevalent among blacks. Salt sensitivity is common, and sodium restriction should be encouraged. Although the magnitude of the blood-pressure response to monotherapy with a diuretic or a calcium-channel antagonist may be greater than the response to monotherapy with another agent, significant reductions occur with ACE inhibitors, angiotensin-receptor antagonists, and beta-blockers when an adequate dose is given.38
Side effects differ according to the class of antihypertensive drug (Table 3). Although adverse effects are reported by 10 to 20 percent of patients taking such drugs, the quality of life improves when hypertension is treated.21 The Treatment of Mild Hypertension Study and the Department of Veterans Affairs Cooperative Study both demonstrated that among the five main classes of antihypertensive drugs (diuretics, beta-blockers, calcium-channel antagonists, ACE inhibitors, and alpha-blockers), no one drug is more acceptable than the others, except that sexual dysfunction is more common among men treated with the diuretic chlorthalidone.21,25 Use of lower-cost, generic drugs that require less frequent doses can improve compliance.
Combination Therapy
The use of lower doses of two or more drugs with complementary mechanisms may lower blood pressure with fewer adverse effects than the use of higher doses of a single agent. Most combination therapies include small doses of a diuretic, which potentiate the effects of other drugs (ACE inhibitors, angiotensin-receptor antagonists, or beta-blockers). Combination therapy may improve compliance and achieve the target blood pressure more rapidly.
Guidelines
National and international groups have issued guidelines for the treatment of hypertension. The main differences among these guidelines are the criteria for initiating drug therapy in low-risk patients with stage 1 hypertension. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure2 and the World Health Organization–International Society of Hypertension41 recommend stratification of patients into risk categories on the basis of age, sex, smoking status, presence or absence of diabetes, cholesterol level, presence or absence of preexisting cardiovascular disease, and presence or absence of target-organ damage (Figure 1). Drug treatment is recommended for stage 1 or higher hypertension if blood pressure does not decrease after a certain period of lifestyle-modification counseling (6 to 12 months, according to the Joint National Committee guidelines). The British Hypertension Society and New Zealand guidelines recommend the use of tables that quantify a person’s 5- or 10-year risk of a cardiovascular event; drugs are recommended only if the 5-year risk is at least 10 percent.42,43 When drugs are indicated, the guidelines recommend those that have been shown to improve cardiovascular outcomes, with coexisting conditions and demographic characteristics taken into account.
Areas of Uncertainty
Although moderate sodium restriction lowers blood pressure, the small effects, variability in response, and lack of a proven cardiovascular benefit have led to uncertainty about whether it should be broadly recommended. There is also uncertainty about whether specific properties of certain drugs result in differential effects on morbidity and mortality that are independent of the reduction in blood pressure.
The use of drugs in patients with a low absolute risk of cardiovascular disease is controversial. The rationale for withholding drugs from such patients is that some trials have shown that mortality among low-risk patients treated with drugs is similar to that in control groups.44 However, given that even high-normal blood pressures (130 to 139/85 to
The appropriate strategy for choosing the initial antihypertensive therapy is still unresolved. Some have proposed that the choice of treatment should be based on renin levels,46 but this approach is not widely used. Whether combination therapy as the initial treatment leads to better control of blood pressure and a lower risk of cardiovascular disease than monotherapy is also unresolved. Finally, optimal blood-pressure targets remain to be determined, particularly for elderly patients.
Conclusions and Recommendations
Hypertension affects 25 percent of adults in the
Persons who have stage 1 hypertension and are at low risk for cardiovascular disease can be treated with lifestyle modifications for up to one year. Patients who have stage 1 hypertension and other cardiovascular risk factors or a higher stage of hypertension should be treated with drugs to reduce blood pressure to a level below 140/90 mm Hg, or to reduce pressure to 130/80 mm Hg or less if the patient has diabetes, renal disease, or both.
Diuretics and beta-blockers are appropriate as first-line therapy for patients without coexisting conditions. ACE inhibitors or angiotensin-receptor antagonists are recommended for patients with type 2 diabetes, kidney disease, or both and are also useful in patients with heart failure. Beta-blockers and ACE inhibitors are recommended in patients with prior myocardial infarction, and calcium-channel antagonists benefit elderly patients at risk for stroke. If blood pressure is not controlled with an optimal dose of a single drug, a second agent with a complementary mechanism of action should be added. Combination therapy provides more rapid control of blood pressure than does monotherapy and is therefore an initial treatment option for patients with stage 2 or 3 hypertension.
Resistant or Difficult–to–Control Hypertension
Case vignette. A 70-year-old woman with a long-standing history of hypertension comes for follow-up. Her medications include atenolol (100 mg daily), hydrochlorothiazide (12.5 mg daily), lisinopril (40 mg daily), and ibuprofen (400 mg twice daily for osteoarthritis). She does not smoke or drink alcohol. Her body-mass index (the weight in kilograms divided by the square of the height in meters) is 32. Her systolic and diastolic blood pressures (measured three times while she was seated) range from 164 to
The Clinical Problem
Resistant, or refractory, hypertension is defined by a blood pressure of at least 140/90 mm Hg or at least 130/80 mm Hg in patients with diabetes or renal disease (i.e., with a creatinine level of more than 1.5 mg per deciliter [133 µmol per liter] or urinary protein excretion of more than 300 mg over a 24-hour period), despite adherence to treatment with full doses of at least three antihypertensive medications, including a diuretic. Patients who have recently received a diagnosis of hypertension or who have not yet received treatment should not be considered to have resistant hypertension, regardless of their blood-pressure level.
Data on the prevalence of resistant hypertension are scant. In large clinical trials of hypertension in which protocols required drug titration until the blood pressure was below a predefined target, the diastolic blood pressure was below
Patients whose hypertension is uncontrolled are more likely to have target-organ damage and a higher long-term cardiovascular risk than are patients whose blood pressure is controlled. Heart failure, stroke, myocardial infarction, and renal failure are related to the degree of the elevation in blood pressure. Other risk factors, such as diabetes and dyslipidemia, further increase the cardiovascular risk in these patients.
Difficult–to–control hypertension is defined here as persistently elevated blood pressure despite treatment with two or three drugs but not meeting the above-mentioned strict criteria for resistant hypertension. Difficult–to–control hypertension is far more common than resistant hypertension.
Strategies and Evidence
Formal studies of the management of resistant or difficult–to–control hypertension are few, and strategies are based largely on observational data from specialty clinics. These series and clinical experiences suggest that a careful evaluation of a patient’s adherence to and adequacy of therapy and lifestyle factors often reveals modifiable contributors to refractory blood pressure; secondary causes (including exogenous substances) must also be considered. A suboptimal medical regimen has been shown to be the primary cause of resistant hypertension in a majority of patients in these studies. Figure 1 outlines a suggested approach to evaluation.
Diagnosis
Blood pressure should be measured after a patient has been seated quietly for five minutes, with his or her arm supported at heart level and with the use of a properly calibrated and sized cuff. If the cuff is too narrow or too short, readings may be erroneously high (typically by 5 to
The diagnosis is based on the findings of at least two or three elevated blood-pressure measurements (in the physician’s office or at home), despite adherence to regimens containing three medications. However, if the blood pressure is above 160/100 mm Hg, additional readings are not necessary for diagnosis. Evaluation (including physical examination and laboratory testing) is routinely warranted to look for evidence of end-organ damage related to hypertension (Table 1) and for other cardiovascular risk factors.1 Volume overload and elevated sympathetic tone, which are common in patients with uncontrolled blood pressure, may occasionally be suggested by the presence of a rapid pulse rate. Renin levels have not been found to be useful in the prediction of excess volume, though they may be useful in the evaluation of possible secondary causes of hypertension.
Some patients who have what appears to be resistant hypertension have a normal blood pressure at home. This phenomenon has been attributed to transitory, or “white-coat,” resistant hypertension in the physician’s office. Repeated home measurements or 24-hour ambulatory monitoring may differentiate this type of hypertension from truly resistant hypertension.13 Such measures are warranted in patients undergoing treatment who have consistently high blood-pressure levels in the physician’s office yet have no evidence of target-organ damage. In one study, as many as a third of patients with apparently resistant hypertension had average blood-pressure levels of less than 130/85 mm Hg on 24-hour or home measurement.14 Some data suggest that blood-pressure values obtained at home or during 24-hour ambulatory procedures correlate better with target-organ involvement, especially left ventricular hypertrophy, than do values obtained in the physician’s office.15 However, office, or white-coat, hypertension is not benign and should not be ignored.
Rarely, in older patients, what appears to be refractory hypertension may represent inaccurate measurement owing to severely sclerotic arteries (i.e., pseudohypertension). The condition is suggested if the radial pulse remains palpable despite occlusion of the brachial artery by the cuff (the Osler maneuver),16 although this sign is not specific. The presence of this condition can be confirmed by intra-arterial blood-pressure measurement.
Adherence to Treatment
Because a diagnosis of resistant hypertension requires a finding of elevated blood pressure despite the use of adequate doses of at least three medications, the patient’s adherence to therapy and the adequacy of the dose should be evaluated routinely. Studies have reported that medication was not increased in more than 50 percent of patients with poorly controlled hypertension despite repeated office visits. Some patients take less than the prescribed dose of medication for economic or other reasons. However, side effects have not been found to be an important reason for a lack of adherence to therapy but may contribute to nonadherence. Signs suggesting nonadherence include missed office visits and a lack of physiological evidence of therapy (e.g., rapid heart rate despite the prescription of beta-blockers or verapamil), but nonadherence is often difficult to recognize or exclude objectively.
Interfering or Exogenous Substances
Patients should be asked routinely about the use of medications or other substances that can elevate blood pressure or antagonize the effects of antihypertensive drugs. These substances include sympathomimetic drugs (e.g., ephedra, phenylephrine, cocaine, and amphetamines), herbal supplements (e.g., ginseng and yohimbine), anabolic steroids, appetite suppressants, and erythropoietin, although all these drugs probably account for less than 2 percent of cases of resistant hypertension. Nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors may raise both systolic and diastolic blood pressure by several mm Hg. These agents impair the excretion of sodium, which causes volume retention; they also inhibit the production of local renal vasodilative prostaglandins; the therapeutic action of angiotensin-converting–enzyme (ACE) inhibitors and loop diuretics (but not calcium-channel blockers) depends on the availability of these prostaglandins.19,20 Efforts should be made to discontinue such agents, although if they are needed for another condition, antihypertensive therapy may need to be modified.
An assessment of dietary and lifestyle factors is also important. Excessive alcohol use (more than three or four drinks per day) and a high sodium intake (typically defined by a urinary sodium excretion of more than 150 mmol per day) may contribute to resistant hypertension; the frequency of salt sensitivity is increased among patients who are at least 60 years of age, patients who are black or obese, and patients with renal impairment. Studies indicate that more than 40 percent of patients with resistant hypertension are obese,23,24 and obese patients may require higher doses of antihypertensive medications than do nonobese patients.
Evaluation of Secondary Hypertension
The possibility that an underlying condition is causing hypertension must also be considered; secondary hypertension is often unmanageable until the underlying cause is treated.11 Among 4000 patients with resistant hypertension who were evaluated during an 18-year period at one tertiary center, secondary causes were found in 10 percent of patients overall and in 17 percent of patients over the age of 60 years.25
Chronic renal parenchymal disease, usually resulting from diabetic nephropathy or hypertensive nephrosclerosis, may be the most common cause of secondary hypertension. Atherosclerotic renovascular disease, which is particularly prevalent among elderly smokers, is another possible cause. The presence of an abdominal bruit or hypokalemia or a recent increase in the severity of hypertension may suggest the diagnosis of atherosclerotic renovascular disease. Screening for renovascular disease may be warranted if other causes of resistant hypertension are not identified, since angioplasty and stenting may improve blood pressure. However, in cases of renovascular hypertension caused by atherosclerotic disease, blood pressure often remains high even after intervention, in contrast to hypertension caused by the much less common fibromuscular dysplasia.
Table 2 summarizes features of and screening tests for these and other causes of secondary hypertension, such as primary aldosteronism (considered to be more common than previously recognized), pheochromocytoma, and sleep apnea (recently recognized to be associated with refractory hypertension). Generally, the decision to screen a patient for such disorders should depend on suggestive findings on history taking, physical examination, or basic laboratory testing. Interventions that are directed at these disorders (e.g., surgery or aldosterone-antagonist therapy for hyperaldosteronism, surgery for pheochromocytoma, and continuous positive airway pressure for sleep apnea) may substantially decrease, although not always normalize, blood pressure. A detailed discussion of all the causes of secondary hypertension is available elsewhere.
Treatment
Patients should routinely be encouraged to reduce their intake of sodium, lose weight (if appropriate), engage in moderate exercise, and reduce their intake of alcohol (to no more than two to three drinks per day). The degree of blood-pressure lowering expected with each of these approaches is often modest but clinically important — for example, 2 to
Adherence to therapy may be increased by the initiation of a system of follow-up reminders or telephone contacts. The involvement of nurses or nurse practitioners, who may have more time than a physician to discuss potential side effects of medications, has been shown to improve patients’ control of their blood pressure. The use of combination therapy (two medications in one pill) may also improve adherence and, in some cases, may reduce the cost of care.
Few data from randomized trials are available to guide the choice of regimen for patients whose blood pressure remains high even though they take several medications; recommendations are based largely on physiological principles and clinical experience. Because volume overload is common among such patients, the most important therapeutic maneuver is generally to add or increase diuretic therapy; more than 60 percent of patients with resistant hypertension may have a response to this approach. Thiazide diuretics are effective in doses of 12.5 to 25.0 mg daily if renal function is normal. Experience suggests that a daily dose of 25 to 50 mg will result in a further decrease in blood pressure. If the glomerular filtration rate is below 30 to 50 ml per minute (or the serum creatinine level is more than 1.5 mg per deciliter), loop diuretics should be used. Short-acting loop diuretics, such as furosemide (at a dose of 20 to 80 mg daily) or bumetanide (at a dose of 0.5 to 2.0 mg daily), must be given two or three times per day. Intermittent natriuresis with once-daily drug administration may lead to reactive sodium retention mediated by the renin–angiotensin system, with consequent inadequate blood-pressure control. Longer-acting diuretics such as torsemide (at 2.5 to 5.0 mg) may be given once a day but are more expensive.
A generally useful strategy is to combine agents from various classes, each of which has one or more of the following effects: a reduction in volume overload (diuretics and aldosterone antagonists), a reduction in sympathetic overactivity (beta-blockers), a decrease in vascular resistance (through the inhibition of the renin–angiotensin system with the use of ACE inhibitors or angiotensin-receptor blockers), the promotion of smooth-muscle relaxation (dihydropyridine calcium-channel blockers and alpha-blockers), and direct vasodilation (hydralazine and minoxidil), although the latter are less well tolerated. An additional medication with a different mechanism of action from others the patient is receiving may further lower the blood pressure or overcome compensatory changes in blood-pressure elevation caused by the first medication without increasing adverse effects. For example, adding a beta-blocker or ACE inhibitor may counteract the stimulation of the renin–angiotensin system by diuretics.34
Some logical combinations include a diuretic with an ACE inhibitor, a beta-blocker, or an angiotensin-receptor blocker or an ACE inhibitor with a calcium-channel blocker. Most patients with resistant hypertension are already receiving combinations of these agents. In these instances, it may be necessary to increase the dose or the frequency of administration from once to twice daily or to include an additional drug, such as an aldosterone antagonist if a patient is already receiving a diuretic, an ACE inhibitor, and a calcium-channel blocker. Certain medications may be preferred if the patient has coexisting illnesses (Table 1 of the Supplementary Appendix, which is available with the full text of this article at www.nejm.org). For example, the addition of an angiotensin-receptor blocker, a beta-blocker, or an aldosterone antagonist would be reasonable if the drug is not already being used in a patient with heart failure.
The Figure below summarizes one approach to the optimization of drug therapy in patients with resistant hypertension. There are limited data to guide whether some agents should be stopped before others are added if multiple drugs are inadequate.
If resistant hypertension persists, patients can augment their therapy with an agent from a different class of drugs. For example, if the patient is receiving an angiotensin-converting–enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB) plus a diuretic and a beta-blocker, a dihydropyridine calcium-channel blocker can be added. If the patient is receiving an ACE inhibitor or an ARB plus a diuretic and a dihydropyridine calcium-channel blocker, a beta-blocker can be added. The practitioner may consider adding an aldosterone antagonist to any of the combinations (but with extreme caution if the patient is receiving an ACE inhibitor or an ARB because of concern regarding hyperkalemia).
Combined alpha- and beta-blockers (labetalol and carvedilol) may improve blood-pressure control. Centrally acting agents — for example, clonidine, 2-adrenergic blockers, reserpine (in low doses), and direct vasodilators (hydralazine or, in rare cases, minoxidil) — may be necessary in some cases, as tolerated. With direct vasodilators, concomitant high-dose beta-blockers (metoprolol or atenolol) and loop diuretics (furosemide) will be needed to counteract reflex tachycardia and edema. Aside from the aldosterone antagonist spironolactone and alpha-blockers, which have been shown to reduce blood pressure in patients with resistant hypertension, data are lacking to predict the magnitude of further blood-pressure reduction associated with the addition of one of these other medications; clinical experience suggests a decrease in systolic pressure of about 5 to
Referral to a hypertension specialist should be considered in patients whose hypertension is difficult to control despite an assessment of adherence, dose, and other factors that may exacerbate the condition — particularly if the use of the above-mentioned combinations is not helpful. In truly refractory cases, other combinations of medications may be considered. Combinations that have been studied include dual diuretic therapy (spironolactone at a dose of 25 to 50 mg daily plus a thiazide at a dose of 12.5 to 50 mg daily or a loop diuretic), which has been associated with a reduction in systolic blood pressure of 20 to
Guidelines
European Society of Hypertension – European Society of Cardiology Guidelines
British Hypertension Society Guidelines IV
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure emphasizes the need to consider secondary causes, improper blood-pressure measurement, volume overload, competing substances, obesity, nonadherence to treatment, inadequate doses or inappropriate combinations of medications, and alcohol consumption as factors in resistant hypertension.1 These guidelines do not include specific recommendations regarding when or how to evaluate patients for specific secondary causes of resistant hypertension or for the management of truly resistant cases.
Areas of Uncertainty
Several questions require further investigation.37 The true prevalence of resistant hypertension remains uncertain. More information is needed to determine the optimal evaluation of patients for secondary hypertension, including indications for screening for hyperaldosteronism, which appears to be underdiagnosed. Data from randomized trials are needed to improve the treatment of patients whose blood pressure remains high while they are receiving multiple agents. In such patients, the possible role of new drugs, such as inhibitors of renin and endothelin-1, requires evaluation.
Summary and Recommendations
The patient in the vignette has elevated blood pressure, despite taking three medications, with evidence of target-organ injury (retinal arteriopathy and left ventricular hypertrophy). Careful assessment of her adherence to therapy is warranted. Such adherence may be improved by addressing the reasons for nonadherence, such as side effects or the cost of medications, or by arranging for more frequent office visits or telephone contact. The ibuprofen she takes for osteoarthritis should probably be discontinued, since it may contribute to blood-pressure elevation, and be replaced with acetaminophen. Weight loss and a restriction of dietary sodium should be encouraged. Since volume overload is common in refractory hypertension, she could increase her dose of diuretic (with repletion of potassium as needed). If these interventions are ineffective, a different class of drug (e.g., a calcium-channel blocker) could be added, and the patient could be screened for renovascular hypertension, even though in patients with this condition, blood pressure may remain elevated despite intervention. Regular follow-up is warranted, with a goal of maintaining the blood pressure below 140/90 mm Hg.
Hypertensive Retinopathy
Hypertensive retinopathy is a condition characterized by a spectrum of retinal vascular signs in people with elevated blood pressure.1 The detection of hypertensive retinopathy with the use of an ophthalmoscope has long been regarded as part of the standard evaluation of persons with hypertension.2,3,4 This clinical practice is supported by both previous5 and current6 reports of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), which list retinopathy as one of several markers of target-organ damage in hypertension. On the basis of the JNC criteria, the presence of retinopathy may be an indication for initiating antihypertensive treatment, even in people with stage 1 hypertension (blood pressure, 140 to 159/90 to
Despite the JNC recommendation, the clinical implications of hypertensive retinopathy are unclear. Many physicians do not regularly perform an ophthalmoscopic examination as part of the care they provide to hypertensive patients, nor do they include retinal findings when making decisions about treatment. Furthermore, there is no clear consensus regarding the classification of hypertensive retinopathy or whether a retinal examination is useful for risk stratification.
The evidence in support of the JNC guidelines on retinal findings in hypertension is based on earlier studies that may not have direct relevance to current clinical practice.7,8,9,10 These studies have several important limitations. First, because they involved patients who had uncontrolled and untreated hypertension, generalization to contemporary populations of patients with lower blood-pressure levels may be problematic. Second, retinopathy as defined in these studies was based on a direct ophthalmoscopic examination. This technique has been shown to be unreliable, with high rates of interobserver variability (20 to 42 percent) and intraobserver variability (10 to 33 percent) when used in persons with mild hypertension.11,12 Third, although many earlier studies cite increased mortality among persons with hypertensive retinopathy,8,9,10 few studies have demonstrated associations between hypertensive retinopathy and specific cardiovascular outcomes (e.g., incident stroke and coronary heart disease) or have adequately controlled for relevant confounding factors (e.g., hyperlipidemia and cigarette smoking). Thus, whether hypertensive retinopathy predicts the risk of cardiovascular outcomes independently of other risk indicators has not been examined until recently. The purpose of this review is to appraise recent studies (i.e., from 1990 onward) in regard to the pathophysiology, epidemiology, and cardiovascular associations of hypertensive retinopathy and the evidence that supports its use for risk stratification in persons with hypertension.
Historical Context and Classification
Hypertensive retinopathy was first described by Marcus Gunn in the 19th century in a series of patients with hypertension and renal disease.7 The retinal signs he observed included generalized and focal arteriolar narrowing, arteriovenous nicking, flame-shaped and blot-shaped retinal hemorrhages, cotton-wool spots, and swelling of the optic disk (Figure 1, Figure 2, and Figure 3). In 1939, Keith et al. showed that these signs of retinopathy were predictive of death in patients with hypertension.10 The authors described a widely used classification system that categorized these signs into four groups of increasing severity.
Examples of Mild Hypertensive Retinopathy.Panel A shows arteriovenous nicking (black arrow) and focal narrowing (white arrow). Panel B shows arteriovenous nicking (black arrows) and widening or accentuation (“copper wiring”) of the central light reflex of the arterioles (white arrows).
Examples of Moderate Hypertensive Retinopathy. Panel A shows retinal hemorrhages (black arrows) and a cotton-wool spot (white arrow). Panel B shows cotton-wool spots (white arrows) and arteriovenous nicking (black arrows).
Example of Malignant Hypertensive Retinopathy. Multiple cotton-wool spots (white arrows), retinal hemorrhages (black arrows), and swelling of the optic disk are visible.
However, several reviews of hypertensive retinopathy since 1996 have questioned the usefulness of the classification system by Keith et al. (subsequently modified by Scheie) and its relevance to current clinical practice. The major criticisms of the original and modified classifications are that they do not enable the clinician to distinguish among low retinopathy grades (e.g., grade 1 signs are not easily distinguished from grade 2 signs) and that the retinopathy grades are not closely correlated with the severity of hypertension. Furthermore, a detailed categorization of retinopathy into four grades does not appear to be supported by retinal studies with the use of fluorescein angiography.
Pathophysiology
The retinal circulation undergoes a series of pathophysiological changes in response to elevated blood pressure. In the initial, vasoconstrictive stage, there is vasospasm and an increase in retinal arteriolar tone owing to local autoregulatory mechanisms. This stage is seen clinically as a generalized narrowing of the retinal arterioles. Persistently elevated blood pressure leads to intimal thickening, hyperplasia of the media wall, and hyaline degeneration in the subsequent, sclerotic, stage. This stage corresponds to more severe generalized and focal areas of arteriolar narrowing, changes in the arteriolar and venular junctions (i.e., arteriovenous nicking or nipping), and alterations in the arteriolar light reflex (i.e., widening and accentuation of the central light reflex, or “copper wiring”).
This is followed by an exudative stage, in which there is disruption of the blood–retina barrier, necrosis of the smooth muscles and endothelial cells, exudation of blood and lipids, and retinal ischemia. These changes are manifested in the retina as microaneurysms, hemorrhages, hard exudates, and cotton-wool spots. Swelling of the optic disk may occur at this time and usually indicates severely elevated blood pressure (i.e., malignant hypertension). Because better methods for the control of blood pressure are now available in the general population, malignant hypertension is rarely seen. In contrast, other retinal vascular complications of hypertension, such as macroaneurysms and branch-vein occlusions, are not uncommon in patients with chronically elevated blood pressure. The stages of hypertensive retinopathy described here, however, may not be sequential. For example, signs of retinopathy that reflect the exudative stage, such as retinal hemorrhage or microaneurysm, may be seen in eyes that do not have features of the sclerotic stage (e.g., arteriovenous nicking). The exudative signs are nonspecific, since they are seen in diabetes and other conditions.
Epidemiology
Since 1990, there have been seven population-based epidemiologic studies (involving a total of 26,477 participants) of various signs of hypertensive retinopathy. In all seven studies, retinal photographs were used to define specific signs of retinopathy without regard to a predetermined grading system. All of the studies were conducted in the general community and included persons with and those without a history of hypertension.
In general, these studies show that signs of hypertensive retinopathy can be reliably identified with a standardized examination of photographs of the fundus. Reproducibility was substantial for the grading of retinal hemorrhages and microaneurysms (e.g., =0.80 to 0.99) and fair to moderate for the grading of arteriovenous nicking and focal arteriolar narrowing (=0.40 to 0.79). In four populations, generalized arteriolar narrowing was estimated from an assessment of retinal vessel diameters with the use of digitized photographs. This technique appears to have substantial reproducibility (i.e., the intraclass correlation coefficient ranged from 0.80 to
On the basis of photographic grading, these epidemiologic studies show that signs of hypertensive retinopathy are common in people 40 years of age or older, even in those without a history of hypertension. Prevalence rates ranged from 2 to 15 percent for various signs of retinopathy, in contrast to the earlier report from the Framingham Eye Study that found a prevalence of less than 1 percent among participants who underwent an ophthalmoscopic examination with dilation. The higher rates of prevalence in these more recent studies are probably due to a higher sensitivity of photography, as compared with clinical ophthalmoscopy, for detecting certain signs of retinopathy. However, there have beeo studies that have directly compared the sensitivity or reliability of photography with that of ophthalmoscopy for the detection of hypertensive retinopathy, as there have been for diabetic retinopathy.
A higher prevalence of retinopathy has been reported among black persons than among whites, a difference that is explained in large part by the higher levels of blood pressure among blacks. The racial variation confirms the results of a previous population-based survey that used direct ophthalmoscopy34 and suggests that retinal examination may be particularly useful for risk stratification among blacks. Variations in the prevalence of specific signs of hypertensive retinopathy according to age and sex have not been consistently demonstrated. There have been fewer studies of the incidence of hypertensive retinopathy. Two studies indicate that the incidence of various signs of retinopathy over a period of five to seven years ranges from 6 to 10 percent.
Blood Pressure
Numerous studies have confirmed the strong association between the presence of signs of hypertensive retinopathy and elevated blood pressure. Two studies have further evaluated the effect of a history of elevated blood pressure on the occurrence of specific retinal signs. In both studies, generalized retinal arteriolar narrowing and arteriovenous nicking were associated with an elevation in blood pressure that had been documented six to eight years before the retinal assessment; the studies were controlled for concurrent blood-pressure levels. This association suggests that generalized narrowing and arteriovenous nicking are markers of vascular damage from chronic hypertension. In contrast, other signs (focal arteriolar narrowing, retinal hemorrhages, microaneurysms, and cotton-wool spots) were related to current but not previous blood-pressure levels and may therefore be more indicative of the severity of recent hypertension.
Furthermore, the observation of signs of retinopathy in people without a known history of hypertension suggests that these signs may be markers of a prehypertensive state. For example, generalized and focal narrowing of the retinal arterioles has been shown to predict the risk of hypertension iormotensive persons.38 Other factors unrelated to hypertension (e.g., hyperglycemia, inflammation, and endothelial dysfunction24) may also be involved in the pathogenesis of retinopathy.
The Risk of Stroke
The strongest evidence of the usefulness of an evaluation of hypertensive retinopathy for risk stratification is based on its association with stroke. It is well known that the retinal circulation shares anatomical, physiological, and embryologic features with the cerebral circulation. An autopsy study of patients with stroke showed a close correlation between retinal and cerebral arteriolar findings. Functional alterations in retinal blood flow in patients with lacunar stroke have also been reported.40
Epidemiologic data from four large, population-based studies showed independent associations between signs of hypertensive retinopathy, as defined by the findings on retinal photographs, and the risk of stroke. The Atherosclerosis Risk in Communities study, a multisite cohort study, showed that some signs of retinopathy (e.g., retinal hemorrhages, microaneurysms, and cotton-wool spots) were associated with a risk of newly diagnosed clinical stroke that was two to four times as high as that for patients who did not have these signs, even when the analysis was controlled for the effects of long-term elevations in blood pressure, cigarette smoking, elevated lipid levels, and other risk factors for stroke. This study has also shown that signs of retinopathy are associated with reduced cognitive performance on standardized neuropsychological tests, cerebral white-matter lesions, and cerebral atrophy as defined on the basis of findings on magnetic resonance imaging (MRI).
In the Atherosclerosis Risk in Communities study, the five-year relative risk of stroke among participants who had both hyperte