Michael Sutters, MD, MRCP (UK)
An estimated 77.9 million Americans have elevated blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥ 90 mm Hg); of these, 78% are aware of their diagnosis, but only 68% are receiving treatment and only 64% of those treated are under control (using the threshold criterion of 140/90 mm Hg). By convention, hypertension is categorized based on office measurements as stage 1 (140–159/90–99 mm Hg) and stage 2 (> 160/100 mm Hg). Cardiovascular morbidity and mortality increase as both systolic and diastolic blood pressures rise, but in individuals over age 50 years, the systolic pressure and pulse pressure are better predictors of complications than diastolic pressure. The prevalence of hypertension increases with age, and it is more common in blacks than in whites. The mortality rates for stroke and coronary heart disease, two of the major complications of hypertension, have declined by 50–60% over the past three decades but have recently leveled off. The number of patients with end-stage kidney disease and heart failure—two other conditions in which hypertension plays a major causative role—continues to rise.
HOW IS BLOOD PRESSURE MEASURED & HYPERTENSION DIAGNOSED?
Blood pressure should be measured with a well-calibrated sphygmomanometer. The bladder width within the cuff should encircle at least 80% of the arm circumference. Readings should be taken after the patient has been resting comfortably, back supported in the sitting or supine position, for at least 5 minutes and at least 30 minutes after smoking or coffee ingestion. A video demonstrating the correct technique can be found at http://www.abdn.ac.uk/medical/bhs/tutorial/tutorial.htm. Office-based devices that permit multiple automated measurements after a pre-programmed rest period produce blood pressure readings that are independent of the white coat effect and digit preference. Blood pressure measurements taken outside the office environment, either by intermittent self monitoring (home blood pressure) or with an automated device programmed to take measurements at regular intervals (ambulatory blood pressure) are more powerful predictors of outcomes and are increasingly advocated in clinical guidelines. Home measurements are also helpful in differentiating “white coat” hypertension (where blood pressure is elevated in the clinic but normal at home) from hypertension that is resistant to treatment and in diagnosis of “masked hypertension” (where blood pressure is normal in the clinic but elevated at home). The cardiovascular risk associated with masked hypertension is similar to that observed in sustained hypertension.
A single elevated blood pressure reading is not sufficient to establish the diagnosis of hypertension. The major exceptions to this rule are hypertensive presentations with unequivocal evidence of life-threatening end-organ damage, as seen in hypertensive emergency, or in hypertensive urgency where blood pressure is > 220/125 mm Hg but life-threatening end-organ damage is absent. In less severe cases, the diagnosis of hypertension depends on a series of measurements of blood pressure, since readings can vary and tend to regress toward the mean with time. Patients whose initial blood pressure is in the hypertensive range exhibit the greatest fall toward the normal range between the first and second encounters. However, the concern for diagnostic precision needs to be balanced by an appreciation of the importance of establishing the diagnosis of hypertension as quickly as possible, since a 3-month delay in treatment of hypertension in high-risk patients is associated with a twofold increase in cardiovascular morbidity and mortality. The Canadian Hypertension Education Program provides an algorithm designed to expedite the diagnosis of hypertension (Figure 11–1). To this end, these guidelines recommend short intervals between initial office visits and stress the importance of early identification of target organ damage or diabetes mellitus, which, if present, justifies pharmacologic intervention if blood pressure remains above 140/90 mm Hg after just two visits. The Canadian guidelines suggest the use of ambulatory and home blood pressure measurements as complements to office-based evaluations. Guidelines from the United Kingdom go further in suggesting that ambulatory or home BP measurements should be used in preference to office-based measurements in the diagnosis of hypertension. When measured by automated office devices, manual home cuffs, or daytime ambulatory equipment, stage 1 hypertension is diagnosed at an average blood pressure > 135/85 mm Hg; for 24-hour ambulatory measurement, the diagnostic threshold for stage 1 hypertension is still lower at 130/80 mm Hg.
Figure 11–1. The Canadian Hypertension Education Program expedited assessment and diagnosis of patients with hypertension: Focus on validated technologies for blood pressure (BP) assessment. (Reprinted, with permission, from the Canadian Hypertension Education Program. The 2012 Canadian Hypertension Education Program recommendations for the management of hypertension: blood pressure management, diagnosis, assessment of risk, and therapy. http://www.hypertension.ca)
Ambulatory blood pressure readings are normally lowest at night and the loss of this nocturnal dip is a dominant predictor of cardiovascular risk, particularly risk of thrombotic stroke. An accentuation of the normal morning increase in blood pressure is associated with increased likelihood of cerebral hemorrhage. Furthermore, variability of systolic blood pressure predicts cardiovascular events independently of mean systolic blood pressure. It is becoming increasingly clear that in diagnosing and monitoring hypertension, there should be a move away from isolated office readings and toward a more integrated view based on repeated measurements in a more “real world” environment. The diagnosis of hypertension does not automatically entail drug treatment; this decision depends on the clinical setting, as discussed below.
Data from the Framingham cohort indicate that blood pressure bears a linear relationship with cardiovascular risk down to a systolic blood pressure of 115 mm Hg; based on these data, it has been suggested that individuals with blood pressures in the gray area of 120–139/80–89 mm Hg be categorized as having “prehypertension.” Because prehypertension often develops into hypertension (50% of affected individuals do so within 4 years), prehypertensive patients should be monitored annually.
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McCormack T et al. Management of hypertension in adults in primary care: NICE guideline. Br J Gen Pract. 2012 Mar;62(596):163–4. [PMID: 22429432]
Pimenta E et al. Prehypertension: epidemiology, consequences and treatment. Nat Rev Nephrol. 2010 Jan;6(1):21–30. [PMID: 19918256]
Sidney S et al; National Forum for Heart Disease and Stroke Prevention. The “heart disease and stroke statistics—2013 update” and the need for a national cardiovascular surveillance system. Circulation. 2013 Jan 1;127(1):21–3. [PMID: 23239838]
Stern HR. The new hypertension guidelines. J Clin Hypertens (Greenwich). 2013 Oct;15(10):748–51. [PMID: 24088284]
Yano Y et al. Recognition and management of masked hypertension: a review and novel approach. J Am Soc Hypertens. 2013 May–Jun;7(3):244–52. [PMID: 23523411]
Approach to Hypertension
Etiology & Classification
Essential hypertension is the term applied to the 95% of hypertensive patients in which elevated blood pressure results from complex interactions between multiple genetic and environmental factors. The proportion regarded as “essential” will diminish with improved detection of clearly defined secondary causes and with better understanding of pathophysiology. Essential hypertension occurs in 10–15% of white adults and 20–30% of black adults in the United States. The onset is usually between ages 25 and 50 years; it is uncommon before age 20 years. The best understood endogenous and environmental determinants of blood pressure include overactivation of the sympathetic nervous and renin-angiotensin-aldosterone systems, blunting of the pressure-natriuresis relationship, variation in cardiovascular and renal development, and elevated intracellular sodium and calcium levels.
Exacerbating factors include obesity, sleep apnea, increased salt intake, excessive alcohol use, cigarette smoking, polycythemia, nonsteroidal anti-inflammatory (NSAID) therapy, and low potassium intake. Obesity is associated with an increase in intravascular volume, elevated cardiac output, activation of the renin-angiotensin system and, probably, increased sympathetic outflow. Weight reduction lowers blood pressure modestly. In patients with sleep apnea, treatment with continuous positive airway pressure (CPAP) has been associated with improvements in blood pressure. Increased salt intakeprobably elevates blood pressure in some individuals so dietary salt restriction is recommended in patients with hypertension (see below).
Excessive use of alcohol also raises blood pressure, perhaps by increasing plasma catecholamines. Hypertension can be difficult to control in patients who consume more than 40 g of ethanol (two drinks) daily or drink in “binges.” Cigarette smoking raises blood pressure, again by increasing plasma norepinephrine. Although the long-term effect of smoking on blood pressure is less clear, the synergistic effects of smoking and high blood pressure on cardiovascular risk are well documented. The relationship of exercise to hypertension is variable. Aerobic exercise lowers blood pressure in previously sedentary individuals, but increasingly strenuous exercise in already active subjects has less effect. The relationship between stress and hypertension is not established. Polycythemia, whether primary, drug-induced, or due to diminished plasma volume, increases blood viscosity and may raise blood pressure. NSAIDs produce increases in blood pressure averaging 5 mm Hg and are best avoided in patients with borderline or elevated blood pressures. Low potassium intake is associated with higher blood pressure in some patients; an intake of 90 mmol/d is recommended.
The complex of abnormalities termed the “metabolic syndrome” (upper body obesity, insulin resistance, and hypertriglyceridemia) is associated with both the development of hypertension and an increased risk of adverse cardiovascular outcomes. Affected patients usually also have low high-density lipoprotein (HDL) cholesterol levels and elevated catecholamines and inflammatory markers such as C-reactive protein.
Approximately 5% of patients have hypertension secondary to identifiable specific causes (Table 11–1). Secondary hypertension should be suspected in patients in whom hypertension develops at an early age or after the age of 50 years, and in those previously well controlled who become refractory to treatment. Hypertension resistant to three medications is another clue although multiple medications are usually required to control hypertension in persons with diabetes. Secondary causes include genetic syndromes, kidney disease, renal vascular hypertension, primary hyperaldosteronism, Cushing syndrome, pheochromocytoma, coarctation of the aorta, and hypertension associated with pregnancy, estrogen use, hypercalcemia and medications.
Table 11–1. Identifiable causes of hypertension.
Renal vascular hypertension should be suspected in the following circumstances: (1) if the documented onset is before age 20 or after age 50 years, (2) hypertension is resistant to three or more drugs, (3) if there are epigastric or renal artery bruits, (4) if there is atherosclerotic disease of the aorta or peripheral arteries (15–25% of patients with symptomatic lower limb atherosclerotic vascular disease have renal artery stenosis), (5) if there is an abrupt increase (> 25%) in the level of serum creatinine after administration of angiotensin-converting enzyme (ACE) inhibitors, or (6) if episodes of pulmonary edema are associated with abrupt surges in blood pressure. There is no ideal screening test for renal vascular hypertension. If suspicion is sufficiently high and endovascular intervention is a viable option, renal arteriography, the definitive diagnostic test, is the best approach. Renal arteriography is not recommended as a routine adjunct to coronary studies. Where suspicion is moderate to low, noninvasive angiography using magnetic resonance (MR) or CT are reasonable approaches. With improvements in technology and operator expertise, Doppler sonography may play an increasing role in detection of renal artery stenosis, providing physiologic indices of stenosis severity and ease of repeated examination to detect progression. Gadolinium, a contrast agent used in MR angiography, is contraindicated in patients with an estimated glomerular filtration rate (GFR) of < 30 mL/min because it might precipitate nephrogenic systemic fibrosis in patients with advanced kidney disease. In young patients with fibromuscular disease, angioplasty is very effective, but there is controversy regarding the best approach to the treatment of atheromatous renal artery stenosis. Correction of the stenosis in selected patients might reduce the number of medications required to control blood pressure and could protect kidney function, but the extent of preexisting parenchymal damage to the affected and contralateral kidney has a significant influence on both blood pressure and kidney function outcomes following revascularization. The real challenge is identifying those patients likely to benefit from intervention: in this regard, a hyperemic (papaverine-induced) systolic gradient > 21 mm Hg appears to predict a good response to renal artery angioplasty or stenting. A reasonable approach advocates medical therapy as long as hypertension can be well controlled and there is no progression of kidney disease. The addition of a statin should be considered. Endovascular intervention might be considered in patients with uncontrollable hypertension, progressive kidney disease, or episodic pulmonary edema attributable to the lesion. Angioplasty might also be warranted when progression of stenosis is either demonstrated or is predicted by a constellation of risk factors, including systolic blood pressure > 160 mm Hg, advanced age, diabetes mellitus or high-grade stenosis (> 60%) at the time of diagnosis. However, multiple studies have failed to identify an overall advantage of stenting over medical management in patients with atherosclerotic renal artery stenosis. The CORAL study utilized a distal capture device to prevent embolization into the kidney, but the conclusion was once again that stenting is not superior to medical therapy (incorporating a statin) in the management of atherosclerotic renal artery stenosis. Although drugs modulating the renin-angiotensin system have improved the success rate of medical therapy of hypertension due to renal artery stenosis, they may trigger hypotension and (usually reversible) kidney dysfunction in individuals with bilateral disease. Thus, kidney function and blood pressure should be closely monitored during the first weeks of therapy in patients in whom this is a consideration.
During the workup for hyperaldosteronism, medications that alter renin and aldosterone levels, including ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, beta-blockers, and clonidine, should be discontinued for 2 weeks before sampling; spironolactone and eplerenone should be held for 4 weeks. Calcium channel and alpha-receptor blockers can be used to control blood pressure during this drug washout period. Patients with a plasma aldosterone level > 16 ng/dL and an aldosterone/renin ratio of ≥ 30 might require further evaluation for primary hyperaldosteronism.
Diagnosis and treatment of Cushing syndrome are discussed in Chapter 26.
When to Refer
Referral to a hypertension specialist should be considered in cases of severe, resistant or early-/late-onset hypertension or when secondary hypertension is suggested by screening.
Chrysant SG. The current status of angioplasty of atherosclerotic renal artery stenosis for the treatment of hypertension. J Clin Hypertens (Greenwich). 2013 Sep;15(9):694–8. [PMID: 24034664]
Cooper CJ et al; the CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2013 Nov18. 2014 Jan 2;370(1):13–22. [PMID: 24245566]
Manger WM. The protean manifestations of pheochromocytoma. Horm Metab Res. 2009 Sep;41(9):658–63. [PMID: 19242899]
Messerli FH et al. Essential hypertension. Lancet. 2007 Aug 18;370(9587):591–603. [PMID: 17707755]
Xia Y et al. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond. Circ Res. 2013 Jun 21;113(1):78–87. [PMID: 23788505]
Complications of Untreated Hypertension
Elevated blood pressure results in structural and functional changes in the vasculature and heart. Most of the adverse outcomes in hypertension are associated with thrombosis rather than bleeding, possibly because increased vascular shear stress converts the normally anticoagulant endothelium to a prothrombotic state. The excess morbidity and mortality related to hypertension approximately doubles for each 6 mm Hg increase in diastolic blood pressure. However, target-organ damage varies markedly between individuals with similar levels of office hypertension; home and ambulatory pressures are superior to office readings in the prediction of end-organ damage and variability in blood pressure from visit to visit predicts cardiovascular endpoints independently of mean office-based systolic blood pressure.
Cardiac complications are the major causes of morbidity and mortality in primary (essential) hypertension. For any level of blood pressure, left ventricular hypertrophy is associated with incremental cardiovascular risk in association with heart failure (through systolic or diastolic dysfunction), ventricular arrhythmias, myocardial ischemia, and sudden death.
The occurrence of heart failure is reduced by 50% with antihypertensive therapy. Hypertensive left ventricular hypertrophy regresses with therapy and is most closely related to the degree of systolic blood pressure reduction. Diuretics have produced equal or greater reductions of left ventricular mass when compared with other drug classes. Conventional beta-blockers are less effective in reducing left ventricular hypertrophy but play a specific role in patients with established coronary artery disease or impaired left ventricular function.
Hypertension is the major predisposing cause of hemorrhagic and ischemic stroke. Cerebrovascular complications are more closely correlated with systolic than diastolic blood pressure. The incidence of these complications is markedly reduced by antihypertensive therapy. Preceding hypertension is associated with a higher incidence of subsequent dementia of both vascular and Alzheimer types. Home and ambulatory blood pressure may be a better predictor of cognitive decline than office readings in older people. Effective blood pressure control may reduce the risk of development of cognitive dysfunction later in life, but once cerebral small vessel disease is established, low blood pressure might exacerbate this problem.
Chronic hypertension leads to nephrosclerosis, a common cause of kidney disease that is particularly prevalent in blacks, in whom susceptibility is linked to APOL1 mutations. These mutations became prevalent in people of African descent because they also conferred resistance to trypanosomal infection. Aggressive blood pressure control, to 130/80 mm Hg or lower, slows the progression of all forms of chronic kidney disease, especially when proteinuria is present.
Hypertension is a contributing factor in many patients with dissection of the aorta. Its diagnosis and treatment are discussed in Chapter 12.
Most Americans with hypertension die of complications of atherosclerosis, but antihypertensive therapy seems to have a lesser impact on atherosclerotic complications compared with the other effects of treatment outlined above. Prevention of cardiovascular outcomes related to atherosclerosis probably requires control of multiple risk factors, of which hypertension is only one.
Duron E et al. Antihypertensive treatments, cognitive decline, and dementia. J Alzheimers Dis. 2010;20(3):903–14. [PMID: 20182022]
White WB et al. Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. Circulation. 2011 Nov 22;124(21):2312–9. [PMID: 22105196]
The clinical and laboratory findings are mainly referable to involvement of the target organs: heart, brain, kidneys, eyes, and peripheral arteries.
Mild to moderate primary (essential) hypertension is largely asymptomatic for many years. The most frequent symptom, headache, is also very nonspecific. Accelerated hypertension is associated with somnolence, confusion, visual disturbances, and nausea and vomiting (hypertensive encephalopathy).
Hypertension in patients with pheochromocytomas that secrete predominantly norepinephrine is usually sustained but may be episodic. The typical attack lasts from minutes to hours and is associated with headache, anxiety, palpitation, profuse perspiration, pallor, tremor, and nausea and vomiting. Blood pressure is markedly elevated, and angina or acute pulmonary edema may occur. In primary aldosteronism, patients may have muscular weakness, polyuria, and nocturia due to hypokalemia; malignant hypertension is rare. Chronic hypertension often leads to left ventricular hypertrophy and diastolic dysfunction, which can present with exertional and paroxysmal nocturnal dyspnea. Cerebral involvement causes stroke due to thrombosis or hemorrhage from microaneurysms of small penetrating intracranial arteries. Hypertensive encephalopathy is probably caused by acute capillary congestion and exudation with cerebral edema, which is reversible.
Like symptoms, physical findings depend on the cause of hypertension, its duration and severity, and the degree of effect on target organs.
Figure 11–2. This image shows severe acute hypertensive retinopathy with hypertensive retinopathy, intraretinal hemorrhages, nerve fiber layer infarcts (cotton-wool spots) and arteriovenous nicking. Retinal arteries show irregular thinning. (Used, with permission, from Courtney E. Francis, MD, Department of Ophthalmology, University of Washington School of Medicine.)
Recommended testing includes the following: hemoglobin; urinalysis and serum creatinine; fasting blood sugar level (hypertension is a risk factor for the development of diabetes, and hyperglycemia can be a presenting feature of pheochromocytoma); plasma lipids (necessary to calculate cardiovascular risk and as a modifiable risk factor); serum uric acid (hyperuricemia is a relative contraindication to diuretic therapy); and serum electrolytes.
Electrocardiographic criteria are highly specific but not very sensitive for left ventricular hypertrophy. The “strain” pattern of ST–T wave changes is a sign of more advanced disease and is associated with a poor prognosis. A chest radiograph is not necessary in the workup for uncomplicated hypertension.
The primary role of echocardiography should be to evaluate patients with clinical symptoms or signs of cardiac disease.
Additional diagnostic studies are indicated only if the clinical presentation or routine tests suggest secondary or complicated hypertension. These may include 24-hour urine free cortisol, urine or plasma metanephrines and plasma aldosterone and renin concentrations to screen for endocrine causes of hypertension. Renal ultrasound will detect structural changes (such as polycystic kidneys, asymmetry and hydronephrosis) as well as echogenicity and reduced cortical volume, which are reliable indicators of advanced chronic kidney disease. Evaluation for renal artery stenosis should be undertaken in concert with subspecialist consultation.
Since most hypertension is essential or primary, few studies are necessary beyond those listed above. If conventional therapy is unsuccessful or if secondary hypertension is suspected, further studies and perhaps referral to a hypertension specialist are indicated.
DellaCroce JT. Hypertension and the eye. Curr Opin Ophthalmol. 2008 Nov;19(6):493–8. [PMID: 18854694]
Lifestyle modification may have an impact on morbidity and mortality. A diet rich in fruits, vegetables, and low-fat dairy foods and low in saturated and total fats (DASH diet) has been shown to lower blood pressure. Additional measures, listed in Table 11–2, can prevent or mitigate hypertension or its cardiovascular consequences.
Table 11–2. Lifestyle modifications to manage hypertension.1
All patients with high-normal or elevated blood pressures, those who have a family history of cardiovascular complications of hypertension, and those who have multiple coronary risk factors should be counseled about nonpharmacologic approaches to lowering blood pressure. Approaches of proved but modest value include weight reduction, reduced alcohol consumption and, in some patients, reduced salt intake. Gradually increasing activity levels should be encouraged in previously sedentary patients, but strenuous exercise training programs in already active individuals may have less benefit. Alternative approaches that may be modestly effective include relaxation techniques and biofeedback. Calcium and potassium supplements have been advocated, but their ability to lower blood pressure is limited. Smoking cessation will reduce cardiovascular risk. Overall, the effects of lifestyle modification on blood pressure are modest.
Aburto NJ et al. Effect of lower sodium intake on health: systematic review and meta-analyses. BMJ. 2013 Apr 3;346:f1326. [PMID: 23558163]
Blumenthal JA et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med. 2010 Jan 25;170(2):126–35. [PMID: 20101007]
Brook RD et al; American Heart Association Professional Education Committee of the Council for High Blood Pressure Research, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, and Council on Nutrition, Physical Activity. Beyond medications and diet: alternative approaches to lowering blood pressure: a scientific statement from the American Heart Association. Hypertension. 2013 Jun;61(6):1360–83. [PMID: 23608661]
Sacks FM et al. Dietary therapy in hypertension. N Engl J Med. 2010 Jun 3;362(22):2102–12. [PMID: 20519681]
Who Should Be Treated with Medications?
Treatment should ideally be offered to all persons in whom blood pressure reduction, irrespective of initial blood pressure levels, will appreciably reduce overall cardiovascular risk with an acceptably low rate of medication-associated adverse effects. Outcomes data indicate that patients with office-based blood pressure measurements that consistently exceed 160/100 mm Hg (stage 2 hypertension) will benefit from antihypertensive therapy irrespective of cardiovascular risk. Several international guidelines suggest that treatment thresholds evaluated by home-based measurements should be lower, perhaps 150/95 mm Hg using home blood pressure or daytime ambulatory measurements. However, prospective outcomes data for treatment based on measurements taken outside the clinic are lacking. As outlined in Figure 11–3, treatment should be offered at lower thresholds in those with elevated cardiovascular risk or in the presence of existing end-organ damage. The corollary of this is that treatment thresholds might reasonably be set higher for young people with extremely low cardiovascular risk; the Canadian guidelines suggest a threshold of > 160/100 mm Hg.
Figure 11–3. British Hypertension Society algorithm for diagnosis and treatment of hypertension, incorporating total cardiovascular risk in deciding which “prehypertensive” patients to treat. (CVD, cardiovascular disease.) CVD risk chart available at qrisk.org. (Reproduced, with permission, from Guidelines for management of hypertension: report of the Fourth Working Party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens. 2004 Mar;18(3):139–85.)
Since evaluation of total cardiovascular risk (Table 11–3) is important in deciding who to treat with antihypertensive medications, risk calculators are becoming essential clinical tools. A reliable and regularly updated calculator is available at Qrisk.org. Free smart phone (eg, iPhone) applications are also available to estimate coronary heart disease risk. In general, a 20% total cardiovascular risk (which includes stroke) is equivalent to a 15% coronary heart disease risk.
Table 11–3. Cardiovascular risk factors.
Goals of Treatment
Most experts believe that blood pressure targets for hypertensive patients at the greatest risk for cardiovascular events, particularly patients with diabetes, should be lower (< 130/80 mm Hg) than for individuals at lower total cardiovascular risk (< 140/90 mm Hg). Observational studies suggest that there does not seem to be a blood pressure level below which decrements in risk taper off. However, this may not be true with respect to pharmacologically modulated blood pressure. In fact, over-enthusiastic treatment may have adverse consequences in certain settings. There is an association between lower blood pressure and cognitive decline in elderly patients subjected to intensification of antihypertensive treatment later in life. Excessive lowering of diastolic pressure, perhaps below 70 mm Hg, should be avoided in patients with coronary artery disease. In diabetic patients, treatment of systolic pressures to below 130–135 mm Hg significantly increases the risk of serious adverse effects with no additional gain in terms of cardiac, renal, or retinal disease. On the other hand, reducing systolic pressure below 130 mm Hg does seem to further lower the risk of stroke, so lower targets might be justified in patients at high risk for cerebrovascular events.
The SPS3 trial in patients recovering from a lacunar stroke indicated that treating the systolic blood pressure to < 130 mm Hg (mean systolic blood pressure of 127 mm Hg among treated vs mean systolic blood pressure 138 mm Hg among untreated patients) probably reduced the risk of recurrent stroke (and with an acceptably low rate of adverse effects from treatment).
Large-scale trials in hypertension have focused on discrete end points occurring over relatively short intervals, thereby placing the emphasis on the prevention of catastrophic events in advanced disease. There is an ongoing shift in emphasis in viewing hypertension in the context of overall cardiovascular risk. Accordingly, treatment of persons with hypertension should focus on comprehensive risk reduction with more careful consideration of the possible long-term adverse effects of antihypertensive medications, which include the metabolic derangements linked to conventional beta-blockers and thiazide diuretics and possible modest elevations in the risk of malignancy associated with several antihypertensive drugs.
Statins should be more widely used. In this respect, there is evidence from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) that statins can significantly improve outcomes in persons with hypertension (with modest background cardiovascular risk) whose total cholesterol is < 250 mg/dL (6.5 mmol/L). Notably, the effect of statins appeared to be synergistic with calcium channel blocker/ACE inhibitor regimens but not beta-blocker/diuretic regimens. The British Hypertension Society guidelines recommend that statins be offered as secondary prevention to patients whose total cholesterol exceeds 135 mg/dL (3.5 mmol/L) if they have documented coronary artery disease or a history of ischemic stroke. In addition, statins should be considered as primary prevention in patients with long-standing type 2 diabetes or in those with type 2 diabetes who are older than age 50 years, and perhaps in all persons with type 2 diabetes. Ideally, total and low-density lipoprotein (LDL) cholesterol should be reduced by 30% and 40% respectively, or to approximately < 155 mg/dL (4 mmol/L) and < 77 mg/dL (2 mmol/L), whichever is the greatest reduction. However, total and LDL cholesterol levels of < 194 mg/dL (5 mmol/L) and < 116 mg/dL (3 mmol/L) respectively, or reductions of 25% and 30% are regarded as clinically acceptable objectives. Low-dose aspirin (81 mg/d) is likely to be beneficial in patients older than age 50 with either target organ damage or elevated total cardiovascular risk (> 20–30%). Care should be taken to ensure that blood pressure is controlled to the recommended levels before starting aspirin to minimize the risk of intracranial hemorrhage.
Bangalore S et al. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose:observations from traditional and bayesian random-effects meta-analyses of randomized trials. Circulation. 2011 Jun 21;123(24):2776–8. [PMID: 21632497]
McInnes G. Pre-hypertension: how low to go and do drugs have a role? Br J Clin Pharmacol. 2012 Feb;73(2):187–93. [PMID: 21883385]
Sever PS et al; ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003 Apr 5;361(9364):1149–58. [PMID: 12686036]
Sever P et al; ASCOT Steering Committee Members. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. 2006 Dec;27(24):2982–8. [PMID: 17145722]
SPS3 Study Group; Benavente OR et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013 Aug 10;382(9891):507–15. Erratum in: Lancet. 2013 Aug 10;382(9891):506. [PMID: 23726159]
Turnbull F et al; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005 Jun 27;165(12):1410–9. [PMID: 15983291]
DRUG THERAPY: CURRENT ANTIHYPERTENSIVE AGENTS
There are now many classes of antihypertensive drugs of which six (diuretics, beta-blockers, renin inhibitors, ACE inhibitors, calcium channel blockers, and ARBs) are suitable for initial therapy based on efficacy and tolerability (Table 11–4). A number of considerations enter into the selection of the initial regimen for a given patient. These include the weight of evidence for beneficial effects on clinical outcomes, the safety and tolerability of the drug, its cost, demographic differences in response, concomitant medical conditions, and lifestyle issues. The specific classes of antihypertensive medications are discussed below, and guidelines for the choice of initial medications are offered.
Table 11–4. Clinical trial and guideline basis for compelling indications for individual drug classes.1
Thiazide diuretics (Table 11–5) are the antihypertensives that have been most extensively studied and most consistently effective in clinical trials. They lower blood pressure initially by decreasing plasma volume, but during long-term therapy, their major hemodynamic effect is reduction of peripheral vascular resistance. Most of the antihypertensive effect of these agents is achieved at lower dosages than used previously (typically, 12.5 mg of hydrochlorothiazide or equivalent), but their biochemical and metabolic effects are dose related. Chlorthalidone has the advantage of better 24-hour blood pressure control than hydrochlorothiazide. The loop diuretics (such as furosemide) may lead to electrolyte and volume depletion more readily than the thiazides and have short durations of action. Because of these adverse effects, loop diuretics should be reserved for use in patients with kidney dysfunction (serum creatinine > 2.5 mg/dL [208.3 mcmol/L]) in which case they are more effective than thiazides. Relative to beta-blockers and ACE inhibitors, diuretics are more potent in blacks, older individuals, the obese, and other subgroups with increased plasma volume or low plasma renin activity (or both). They are relatively more effective in smokers than in nonsmokers. Long-term thiazide administration also mitigates the loss of bone mineral content in older women at risk for osteoporosis.
Table 11–5. Antihypertensive drugs: Diuretics. (In descending order of preference.)
Overall, diuretics administered alone control blood pressure in 50% of patients with mild to moderate hypertension and can be used effectively in combination with all other agents. They are also useful for lowering isolated or predominantly systolic hypertension. The adverse effects of diuretics relate primarily to the metabolic changes listed in Table 11–5. Erectile dysfunction, skin rashes, and photosensitivity are less frequent. Hypokalemia has been a concern but is uncommon at the recommended dosages. The risk can be minimized by limiting dietary salt or increasing dietary potassium; potassium replacement is not usually required to maintain serum K+ at > 3.5 mmol/L. Higher serum K levels are prudent in patients at special risk from intracellular potassium depletion, such as those taking digoxin or with a history of ventricular arrhythmias in which case a potassium-sparing agent could be used. Compared with ACE inhibitors and ARBs, diuretic therapy is associated with a slightly higher incidence of mild new-onset diabetes. Diuretics also increase serum uric acid and may precipitate gout. Increases in blood glucose, triglycerides, and LDL cholesterol may occur but are relatively minor during long-term low-dose therapy.
These drugs are effective in hypertension because they decrease the heart rate and cardiac output. Even after continued use of beta-blockers, cardiac output remains lower and systemic vascular resistance higher with agents that do not have intrinsic sympathomimetic or alpha-blocking activity. The beta-blockers also decrease renin release and are more efficacious in populations with elevated plasma renin activity, such as younger white patients. They neutralize the reflex tachycardia caused by vasodilators and are especially useful in patients with associated conditions that benefit from the cardioprotective effects of these agents. These include individuals with angina pectoris, previous myocardial infarction, and stable heart failure as well as those with migraine headaches and somatic manifestations of anxiety.
Although all beta-blockers appear to be similar in antihypertensive potency, they differ in a number of pharmacologic properties (these differences are summarized in Table 11–6), including specificity to the cardiac beta-1-receptors (cardioselectivity) and whether they also block the beta-2-receptors in the bronchi and vasculature; at higher dosages, however, all agents are nonselective. The beta-blockers also differ in their pharmacokinetics, lipid solubility—which determines whether they cross the blood–brain barrier and affect the incidence of central nervous system side effects—and route of metabolism. Unlike the traditional beta-blockers, carvedilol and nebivolol also diminish peripheral vascular resistance through concomitant alpha-blockade and increased nitric oxide release, respectively. The implications of this distinction are discussed below.
Table 11–6. Antihypertensive drugs: Beta-adrenergic blocking agents.
The side effects of beta-blockers include inducing or exacerbating bronchospasm in predisposed patients; sinus node dysfunction and atrioventricular (AV) conduction depression (resulting in bradycardia or AV block); nasal congestion; Raynaud phenomenon; and central nervous system symptoms with nightmares, excitement, depression, and confusion. Fatigue, lethargy, and erectile dysfunction may occur. The traditional beta-blockers (but not the vasodilator beta-blockers carvedilol and nebivolol) have an adverse effect on lipids and glucose metabolism. Metoprolol reduces mortality and morbidity in patients with chronic stable heart failure and systolic left ventricular dysfunction (see Chapter 10). Carvedilol and nebivolol, which maintain cardiac output, are also beneficial in patients with systolic left ventricular dysfunction. Beta-blockers are used cautiously in patients with type 1 diabetes, since they can mask the symptoms of hypoglycemia and prolong these episodes by inhibiting gluconeogenesis. These drugs should also be used with caution in patients with advanced peripheral vascular disease associated with rest pain or nonhealing ulcers, but they are generally well tolerated in patients with mild claudication. Nebivolol can be safely used in patients with stage II claudication (claudication at 200 m).
In treatment of pheochromocytoma, beta-blockers should not be administered until alpha-blockade has been established. Otherwise, blockade of vasodilatory beta-2-adrenergic receptors will allow unopposed vasoconstrictor alpha-adrenergic receptor activation with worsening of hypertension. For the same reason, beta-blockers should not be used to treat hypertension arising from cocaine use.
In addition to adverse metabolic changes associated with their use, some experts have suggested that the therapeutic shortcomings of traditional beta-blockers are the consequence of the particular hemodynamic profile associated with these drugs. Pressure peaks in the aorta are augmented by reflection of pressure waves from the peripheral circulation. These reflected waves are delayed in patients taking ACE inhibitors and thiazide diuretics, resulting in decreased central systolic and pulse pressures. By contrast, traditional beta-blockers appear to potentiate reflection of pressure waves, possibly because peripheral resistance vessels are a reflection point and peripheral resistance is increased by these drugs. This might explain why the traditional beta-blockers are less effective at controlling systolic and pulse pressure.
Because of the lack of efficacy in primary prevention of myocardial infarction and inferiority compared with other drugs in prevention of stroke and left ventricular hypertrophy, traditional beta-blockers should not be regarded as ideal first-line agents in the treatment of hypertension without specific compelling indications (such as active coronary artery disease). It might be that vasodilating beta-blockers will emerge as alternative first-line antihypertensives, but this possibility has yet to be rigorously tested in outcomes studies.
Great care should be exercised if the decision is made, in the absence of compelling indications, to remove beta-blockers from the treatment regimen because abrupt withdrawal can precipitate acute coronary events and severe increases in blood pressure.
Since renin cleavage of angiotensinogen is the rate-limiting step in the renin-angiotensin cascade, the most efficient inactivation of this system would be expected with renin inhibition. Conventional ACE inhibitors and ARBs probably offer incomplete blockade, even in combination. Aliskiren, a renin inhibitor, binds the proteolytic site of renin, thereby preventing cleavage of angiotensinogen. As a consequence, levels of angiotensins I and II are reduced and renin concentration is increased. Aliskiren effectively lowers blood pressure, reduces albuminuria, and limits left ventricular hypertrophy but it has yet to be established as a first-line drug based on outcomes data. The combination of aliskiren with ACE inhibitors or ARBs in persons with type 2 diabetes mellitus certainly offers no advantage and might even increase the risk of adverse cardiac or renal consequences.
ACE inhibitors are being increasingly used as the initial medication in mild to moderate hypertension (Table 11–7). Their primary mode of action is inhibition of the renin–angiotensin–aldosterone system, but they also inhibit bradykinin degradation, stimulate the synthesis of vasodilating prostaglandins, and can reduce sympathetic nervous system activity. These latter actions may explain why they exhibit some effect even in patients with low plasma renin activity. ACE inhibitors appear to be more effective in younger white patients. They are relatively less effective in blacks and older persons and in predominantly systolic hypertension. Although as single therapy they achieve adequate antihypertensive control in only about 40–50% of patients, the combination of an ACE inhibitor and a diuretic or calcium channel blocker is potent.
Table 11–7. Antihypertensive drugs: Renin and ACE inhibitors and angiotensin II receptor blockers.
ACE inhibitors are the agents of choice in persons with type 1 diabetes with frank proteinuria or evidence of kidney dysfunction because they delay the progression to end-stage kidney disease. Many authorities have expanded this indication to include persons with type 1 and type 2 diabetics with microalbuminuria who do not meet the usual criteria for antihypertensive therapy. ACE inhibitors may also delay the progression of nondiabetic kidney disease. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduced the number of cardiovascular deaths, nonfatal myocardial infarctions, and nonfatal strokes and also reduced the incidence of new-onset heart failure, kidney dysfunction, and new-onset diabetes in a population of patients at high risk for vascular events. Although this was not specifically a hypertensive population, the benefits were associated with a modest reduction in blood pressure, and the results inferentially support the use of ACE inhibitors in similar hypertensive patients. ACE inhibitors are a drug of choice (usually in conjunction with a diuretic and a beta-blocker) in patients with heart failure and are indicated also in asymptomatic patients with reduced ejection fraction. An advantage of the ACE inhibitors is their relative freedom from troublesome side effects. Severe hypotension can occur in patients with bilateral renal artery stenosis; sudden increases in creatinine may ensue but are usually reversible with discontinuation of ACE inhibition. Hyperkalemia may develop in patients with kidney disease and type IV renal tubular acidosis (commonly seen in diabetics) and in the elderly. A chronic dry cough is common, seen in 10% of patients or more, and may require stopping the drug. Skin rashes are observed with any ACE inhibitor. Angioedema is an uncommon but potentially dangerous side effect of all agents of this class because of their inhibition of kininase. Exposure of the fetus to ACE inhibitors during the second and third trimesters of pregnancy has been associated with a variety of defects due to hypotension and reduced renal blood flow.
ARBs can improve cardiovascular outcomes in patients with hypertension as well as in patients with related conditions such as heart failure and type 2 diabetes with nephropathy. ARBs have not been compared with ACE inhibitors in randomized controlled trials in patients with hypertension, but two trials comparing losartan with captopril in heart failure and post-myocardial infarction left ventricular dysfunction showed trends toward worse outcomes in the losartan group. By contrast, valsartan seems as effective as ACE inhibitors in these settings, suggesting that ARBs may be heterogeneous with respect to effects beyond blood pressure control. The Losartan Intervention for Endpoints (LIFE) trial in nearly 9000 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy—comparing losartan with the beta-blocker atenolol as initial therapy—demonstrated a significant reduction in stroke with losartan. Of note is that in diabetic patients, death and myocardial infarction were also reduced, and there was a lower occurrence of new-onset diabetes. In this trial, as in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), blacks treated with renin-angiotensin-aldosterone system (RAAS) inhibitors exhibited less blood pressure reduction and less benefit with regard to clinical end points. In the treatment of hypertension, combination therapy with an ACE inhibitor and an ARB is not advised because it generally offers no advantage over monotherapy at maximum dose with addition of a complementary class where necessary.
Unlike ACE inhibitors, the ARBs do not cause cough and are less likely to be associated with skin rashes or angioedema. However, as seen with ACE inhibitors, hyperkalemia can be a problem, and patients with bilateral renal artery stenosis may exhibit hypotension and worsened kidney function. Olmesartan has been linked to a sprue-like syndrome, presenting with abdominal pain, weight loss, and nausea, which subsides upon drug discontinuation.
Spironolactone and eplerenone are natriuretic in sodium-retaining states, such as heart failure and cirrhosis, but only very weakly so in hypertension. These drugs have reemerged in the treatment of hypertension, particularly in resistant patients and are helpful additions to most other antihypertensive medications. Consistent with the increasingly appreciated importance of aldosterone in essential hypertension, the aldosterone receptor blockers are effective at lowering blood pressure in all hypertensive patients regardless of renin level, and are also effective in blacks. Aldosterone plays a central role in target organ damage, including the development of ventricular and vascular hypertrophy and renal fibrosis. Aldosterone receptor antagonists ameliorate these consequences of hypertension, to some extent independently of effects on blood pressure. Spironolactone can cause breast pain and gynecomastia in men through activity at the progesterone receptor, an effect not seen with the more specific eplerenone. Hyperkalemia is a problem with both drugs, chiefly in patients with chronic kidney disease.
These agents act by causing peripheral vasodilation but with less reflex tachycardia and fluid retention than other vasodilators. They are effective as single-drug therapy in approximately 60% of patients in all demographic groups and all grades of hypertension (Table 11–8). For these reasons, they may be preferable to beta-blockers and ACE inhibitors in blacks and older persons. Verapamil and diltiazem should be combined cautiously with beta-blockers because of their potential for depressing AV conduction and sinus node automaticity as well as contractility.
Table 11–8. Antihypertensive drugs: Calcium channel blocking agents.
Initial concerns about possible adverse cardiac effects of calcium channel blockers have been convincingly allayed by several subsequent large studies that have demonstrated that calcium channel blockers are equivalent to ACE inhibitors and thiazide diuretics in prevention of coronary heart disease, major cardiovascular events, cardiovascular death, and total mortality. A protective effect against stroke with calcium channel blockers is well established, and in two trials (ALLHAT and the Systolic Hypertension in Europe trial), these agents appeared to be more effective than diuretic-based therapy.
The most common side effects of calcium channel blockers are headache, peripheral edema, bradycardia, and constipation (especially with verapamil in the elderly). The dihydropyridine agents—nifedipine, nicardipine, isradipine, felodipine, nisoldipine, and amlodipine—are more likely to produce symptoms of vasodilation, such as headache, flushing, palpitations, and peripheral edema. Edema is minimized by coadministration of an ACE inhibitor or ARB. Calcium channel blockers have negative inotropic effects and should be used cautiously in patients with cardiac dysfunction. Amlodipine is the only calcium channel blocker with established safety in patients with severe heart failure. According to a case-control study based in the Pacific Northwest of the United States, calcium channel blockers as a class may increase the risk of breast cancer by 2.5-fold, but this relationship has not been consistently observed in other studies. If this relationship is substantiated, and as the long-term adverse effects of other classes of antihypertensive medications are clarified, guidelines may change. However, it would be premature to alter practices at this time.
Prazosin, terazosin, and doxazosin (Table 11–9) block postsynaptic alpha-receptors, relax smooth muscle, and reduce blood pressure by lowering peripheral vascular resistance. These agents are effective as single-drug therapy in some individuals, but tachyphylaxis may appear during long-term therapy and side effects are relatively common. These include marked hypotension after the first dose which, therefore, should be small and given at bedtime. Post-dosing palpitations, headache, and nervousness may continue to occur during long-term therapy; these symptoms may be less frequent or severe with doxazosin because of its more gradual onset of action. Cataractectomy in patients exposed to alpha-blockers can be complicated by the floppy iris syndrome, even after discontinuation of the drug, so the ophthalmologist should be alerted that the patient has been taking the drug prior to surgery.
Table 11–9. Alpha-adrenoceptor blocking agents, sympatholytics, and vasodilators.
Unlike beta-blockers and diuretics, alpha-blockers have no adverse effect on serum lipid levels—in fact, they increase HDL cholesterol while reducing total cholesterol. Whether this is beneficial in the long term has not been established. In ALLHAT, persons receiving doxazosin as initial therapy had a significant increase in heart failure hospitalizations and a higher incidence of stroke relative to those receiving diuretics, prompting discontinuation of this arm of the study. To summarize, alpha-blockers should generally not be used as initial agents to treat hypertension—except perhaps in men with symptomatic prostatism or nightmares linked to posttraumatic stress disorder.
Methyldopa, clonidine, guanabenz, and guanfacine (Table 11–9) lower blood pressure by stimulating alpha-adrenergic receptors in the central nervous system, thus reducing efferent peripheral sympathetic outflow. These agents are effective as single therapy in some patients, but they are usually used as second- or third-line agents because of the high frequency of drug intolerance, including sedation, fatigue, dry mouth, postural hypotension, and erectile dysfunction. An important concern is rebound hypertension following withdrawal. Methyldopa also causes hepatitis and hemolytic anemia and is avoided except in individuals who have already tolerated long-term therapy. There is considerable experience with methyldopa in pregnant women, and it is still used for this population. Clonidine is available in patches, which may have particular value in patients in whom compliance is a troublesome issue.
Hydralazine and minoxidil (Table 11–9) relax vascular smooth muscle and produce peripheral vasodilation. When given alone, they stimulate reflex tachycardia, increase myocardial contractility, and cause headache, palpitations, and fluid retention. They are usually given in combination with diuretics and beta-blockers in resistant patients. Hydralazine produces frequent gastrointestinal disturbances and may induce a lupus-like syndrome. Minoxidil causes hirsutism and marked fluid retention; this agent is reserved for the most refractory of cases.
These agents are now used infrequently and usually in refractory hypertension. Reserpine remains a cost-effective antihypertensive agent (Table 11–9). Its reputation for inducing mental depression and its other side effects—sedation, nasal stuffiness, sleep disturbances, and peptic ulcers—has made it unpopular, though these problems are uncommon at low dosages. Guanethidine and guanadrel inhibit catecholamine release from peripheral neurons but frequently cause orthostatic hypotension (especially in the morning or after exercise), diarrhea, and fluid retention.
Developing an Antihypertensive Regimen
Historically, data from a number of large trials support the overall conclusion that antihypertensive therapy with diuretics and beta-blockers has a major beneficial effect on a broad spectrum of cardiovascular outcomes, reducing the incidence of stroke by 30–50% and of heart failure by 40–50%, and halting progression to accelerated hypertension syndromes. The decreases in fatal and nonfatal coronary heart disease and cardiovascular and total mortality were less dramatic, ranging from 10% to 15%. Similar placebo-controlled data pertaining to the newer agents are generally lacking, except for stroke reduction with the calcium channel blocker nitrendipine in the Systolic Hypertension in Europe trial. However, there is substantial evidence that ACE inhibitors, and to a lesser extent ARBs, reduce adverse cardiovascular outcomes in other related populations (eg, patients with diabetic nephropathy, heart failure, or postmyocardial infarction and individuals at high risk for cardiovascular events). Most large clinical trials that have compared outcomes in relatively unselected patients have failed to show a difference between newer agents—such as ACE inhibitors, calcium channel blockers, and ARBs—and the older diuretic-based regimens with regard to survival, myocardial infarction, and stroke. Where differences have been observed, they have mostly been attributable to subtle asymmetries in blood pressure control rather than to any inherent advantages of one agent over another. Recommendations for initial treatment identify ACE inhibitors, ARBs, and calcium channel blockers as valid choices. Because of their adverse metabolic profile, initial therapy with thiazides might best be restricted to older patients. Thiazides are acceptable as first-line therapy in blacks because of specific efficacy in this group. Exceptions to these recommendations are appropriate for individuals who have specific (or “compelling”) indications for another class of agent, as outlined in Table 11–4.
As discussed above, beta-blockers should no longer be considered ideal first-line drugs in the treatment of hypertension without compelling indications for their use. Vasodilator beta-blockers (such as carvedilol and nebivolol) may produce better outcomes than traditional beta-blockers; however, this possibility remains a theoretical consideration.
For the purpose of devising an optimal treatment regimen, drugs can be divided into two complementary groups easily remembered as A and CD. A refers to drugs that interrupt the renin-angiotensin system (ACE/ARB/renin inhibitor) and C and D refer to those that do not (calcium channel blockers and thiazide diuretics). Combinations of drugs between these groups are likely to be more potent in lowering blood pressure than combinations within a group. Drugs that interrupt the renin-angiotensin cascade are more effective in young, white persons, in whom renin tends to be higher, and drugs C/Dare more effective in old or black persons, in whom renin levels are generally lower. Figure 11–4 illustrates guidelines for initiating antihypertensive therapy established by the United Kingdom’s National Institute of Health and Clinical Excellence (NICE). In trials that include patients with systolic hypertension, most patients require two or more medications and even then a substantial proportion fail to achieve the goal systolic blood pressure of < 140 mm Hg (<130 mm Hg in high-risk persons). In diabetic patients, three or four drugs are usually required to reduce systolic blood pressure to < 140 mm Hg. In many patients, blood pressure cannot be adequately controlled with any combination. As a result, debating the appropriate first-line agent is less relevant than determining the most appropriate combinations of agents. This has led many experts and practitioners to recommend the use of fixed-dose combination antihypertensive agents as first-line therapy in patients with substantially elevated systolic pressures (> 160/100 mm Hg) or difficult-to-control hypertension (which is often associated with diabetes or kidney dysfunction). Based both on antihypertensive efficacy and complementarity, combinations of an ACE inhibitor or ARB plus a calcium channel blocker or diuretic are recommended. In light of side effect profiles, calcium channel blockers might be preferable to thiazides in the younger hypertensive patient. Furthermore, based on the results from the ACCOMPLISH trial, a combination of ACE inhibitor and calcium channel blocker may also prove optimal for patients at high risk for cardiovascular events. The initial use of low-dose combinations allows faster blood pressure reduction without substantially higher intolerance rates and is likely to be better accepted by patients. However, data from the ALTITUDE study (in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease or both), indicate that the addition of aliskiren to either ARB or ACE inhibitor was associated with worse outcomes and cannot be recommended, at least in this population. A suggested approach to treatment, tailored to patient demographics, is outlined in Table 11–10.
Figure 11–4. Hypertension treatment guidelines from the United Kingdom’s National Institute for Health and Care Excellence. Guidelines identify angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers (CCB) as first-line medications and suggest a sequence of escalating drug therapy depending on blood pressure response. As noted, the choice of the initial agent is influenced by patient demographics. In Step 4, higher doses of thiazide-type diuretics may be used as long as serum potassium levels exceed 4.5 mEq/L. Key: A, ACE inhibitor or ARB; C, calcium-channel blocker; D, diuretic, thiazide-like. (Modified, with permission, from the 2013 hypertension guidelines published by the National Institute for Health and Care Excellence. http://www.nice.org.uk/nicemedia/live/13561/65641/65641.pdf)
Table 11–10. Choice of antihypertensive agent based on demographic considerations.1,2
In sum, as a prelude to treatment, the patient should be informed of common side effects and the need for diligent compliance. In patients with mild or stage 1 hypertension (< 160/90 mm Hg) in whom pharmacotherapy is indicated, treatment should start with a single agent at a low dose. Follow-up visits should usually be at 4- to 6-week intervals to allow for full medication effects to be established (especially with diuretics) before further titration or adjustment. If, after titration to usual doses, the patient has shown a discernible but incomplete response and a good tolerance of the initial drug, a second medication should be added. As a rule of thumb, a blood pressure reduction of 10 mm Hg can be expected for each antihypertensive agent added to the regimen and titrated to the optimum dose. In those with more severe hypertension (stage 2), or with comorbidities (such as diabetes) that are likely to render them resistant to treatment, initiation with combination therapy is advised and more frequent follow-up is indicated.
Patients who are compliant with their medications and who do not respond to conventional combination regimens should usually be evaluated for secondary hypertension before proceeding to more complex regimens.
Special Considerations in the Treatment of Diabetic Hypertensive Patients
Hypertensive patients with diabetes are at particularly high risk for cardiovascular events. More aggressive treatment of hypertension in these patients prevents progressive nephropathy, and a meta-analysis supports the notion that lower treatment goals (< 130–135/80 mm Hg) are especially effective at reducing cardiovascular risk in diabetic patients compared with nondiabetic patients. Blood pressures should probably not be dropped below 120/70 mm Hg. Because of the beneficial effects of ACE inhibitors in diabetic nephropathy, they should be part of the initial treatment regimen. ARBs or perhaps renin inhibitors may be substituted in those intolerant of ACE inhibitors. However, most diabetic patients require combinations of three to five agents to achieve target blood pressure, usually including a diuretic and a calcium channel blocker or beta-blocker. In addition to rigorous blood pressure control, treatment of persons with diabetes should include aggressive treatment of other risk factors.
Treatment of Hypertension in Chronic Kidney Disease
Hypertension is present in 40% of patients with a GFR of 60–90 mL/min, and 75% of patients with a GFR < 30 mL/min. ACE inhibitors and ARBs have been shown to delay progression of kidney disease in persons with type 1 and type 2 diabetes, respectively. It is also likely that inhibition of the renin-angiotensin system protects kidney function in nondiabetic kidney disease associated with significant proteinuria. Combinations of ACE inhibitors and ARBs in persons with atherosclerosis or type 2 diabetes with end organ damage were synergistic with respect to minimizing proteinuria in the ONTARGET study. However, this strategy slightly increased the risk of progression to dialysis and death and is not recommended in this patient population.
As discussed above, the blood pressure target in treating patients with hypertension and nondiabetic chronic kidney disease should generally be < 140/90 mm Hg. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines advocate a lower target of < 130/80 mm Hg in patients with significant proteinuria. Drugs that interrupt the renin-angiotensin cascade are preferred for initial therapy. Transition from thiazide to loop diuretic is often necessary to control volume expansion as kidney function worsens. Evidence has demonstrated that ACE inhibitors remain protective and safe in kidney disease associated with significant proteinuria and serum creatinine as high as 5 mg/dL (380 mcmol/L). Note that such treatment would likely result in acute worsening of kidney function in patients with significant renal artery stenosis, so kidney function and electrolytes should be monitored carefully after introduction of ACE inhibitors. Persistence with ACE inhibitor/ARB therapy in the face of hyperkalemia is probably not warranted, since other antihypertensive medications are renoprotective as long as goal blood pressures are maintained.
Hypertension Management in Blacks
Substantial evidence indicates that blacks are not only more likely to become hypertensive and more susceptible to the cardiovascular and renal complications of hypertension—they also respond differently to many antihypertensive medications. The REGARDS study illustrates these disparities. At systolic blood pressures less than 120 mm Hg, black and white participants between 45 and 64 years of age had equal risk of stroke. For a 10 mm Hg increase in systolic blood pressure, the risk of stroke was threefold higher in black participants. At the level of stage 1 hypertension, the hazard ratio for stroke in black compared to white participants between 45 and 64 years of age was 2.35. This increased susceptibility may reflect genetic differences in the cause of hypertension or the subsequent responses to it, differences in occurrence of comorbid conditions such as diabetes or obesity, or environmental factors such as diet, activity, stress, or access to health care services. In any case, as in all persons with hypertension, a multifaceted program of education and lifestyle modification is warranted. Early introduction of combination therapy has been advocated. Because it appears that ACE inhibitors and ARBs—in the absence of concomitant diuretics—are less effective in blacks than in whites, initial therapy should generally be a diuretic or a diuretic combination with a calcium channel blocker.
Treating Hypertension in the Elderly
Several studies in persons over 60 years of age have confirmed that antihypertensive therapy prevents fatal and nonfatal myocardial infarction and reduces overall cardiovascular mortality. These trials placed the focus on control of systolic blood pressure (the hypertension affecting the majority of those over age 60 is predominantly systolic)—in contrast to the historical emphasis on diastolic blood pressures. Most clinical guidelines suggest that treatment targets for older people (age 60–80 years) should be the same as those for younger individuals (< 140/90 mm Hg), except pressure should be reduced more gradually with a safe intermediate systolic blood pressure goal of 160 mm Hg. In the very elderly, over age 80 years, the HYVET study indicated that a reasonable ultimate systolic blood pressure goal would be 150/80 mm Hg, reflected by the Canadian and European target of < 150/90 mm Hg in this population. The most recent US Joint National Committee Report (JNC8) adopted a rigorous outcomes-based position in recommending a higher treatment goal of < 150/90 mm Hg in persons older than 60 years of age. The same medications are used in older patients, but at 50% lower doses. As treatment is initiated, older patients should be carefully monitored for orthostasis, altered cognition, and electrolyte disturbances. The HYVET trial recruited individuals who were relatively well; by contrast, there appears to be a loss of the usual relationship between blood pressure and morbidity/mortality in the very elderly who are also frail (as defined by a walking speed of less than 0.8 m/sec over 6 m). In the very frail (those unable to walk 6 m), higher blood pressures were paradoxically associated with better outcomes. A less aggressive approach to the treatment of hypertension would therefore seem appropriate in the very elderly who are also frail.
Follow-Up of Patients Receiving Hypertension Therapy
Once blood pressure is controlled on a well-tolerated regimen, follow-up visits can be infrequent and laboratory testing limited to those appropriate for the patient and the medications used. Yearly monitoring of blood lipids is recommended, and an electrocardiogram should be repeated at 2- to 4-year intervals depending on whether initial abnormalities are present, the presence of coronary risk factors, and age. Pharmacy care programs and home blood pressure monitoring have been shown to improve compliance with medications. Patients who have had excellent blood pressure control for several years, especially if they have lost weight and initiated favorable lifestyle modifications, might be considered for a trial of reduced antihypertensive medications.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec18;288(23):2981–97. [PMID: 12479763]
Holdiness A et al. Renin angiotensin aldosterone system blockade: little to no rationale for ACE inhibitor and ARB combinations. Am J Med. 2011 Jan;124(1):15–9. [PMID: 21187182]
Howard G et al. Racial differences in the impact of elevated systolic blood pressure on stroke risk. JAMA Intern Med. 2013 Jan 14;173(1):46–51. [PMID: 23229778]
James PA et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2013 Dec 18. 2014 Feb 5;311(5):507–20. [PMID: 24352797]
Kountz DS. Hypertension in black patients: an update. Postgrad Med. 2013 May;125(3):127–35. [PMID: 23748513]
Lipsitz LA. A 91-year-old woman with difficult-to-control hypertension: a clinical review. JAMA. 2013 Sep 25;310(12):1274–80. [PMID: 24065014]
Parving HH et al; ALTITUDE Investigators. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204–13. [PMID: 23121378]
Wiysonge CS et al. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2012 Nov 14;11:CD002003. [PMID: 23152211]
Resistant hypertension is defined in JNC 7 as the failure to reach blood pressure control in patients who are adherent to full doses of an appropriate three-drug regimen (including a diuretic). Adherence is a major issue: the rate of partial or complete noncompliance probably approaches 50% in this group of patients; doxazosin, spironolactone, and hydrochlorothiazide were particularly unpopular in one study based on drug assay in Eastern Europe. In the approach to resistant hypertension, the clinician should first confirm compliance and rule out “white coat hypertension.” Exacerbating factors should be considered (as outlined above). Finally, identifiable causes of hypertension should be sought (Table 11–11). The clinician should pay particular attention to the type of diuretic being used in relation to the patient’s kidney function. Aldosterone may play an important role in resistant hypertension and aldosterone receptor blockers can be very useful. If goal blood pressure cannot be achieved following completion of these steps, consultation with a hypertension specialist should be considered. Interruption of autonomic reflexes through radiofrequency ablation of renal sympathetic nerves or stimulation of carotid baroreceptors effectively lowers blood pressure in resistant patients but these approaches have yet to be formally evaluated in controlled outcomes-based trials. There is at least one early report of renal artery stenosis linked to the former procedure.
Table 11–11. Causes of resistant hypertension.
Acelajado MC et al. Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment. Cardiol Clin. 2010 Nov;28(4):639–54. [PMID: 20937447]
Böhm M et al. Renal sympathetic denervation: applications in hypertension and beyond. Nat Rev Cardiol. 2013 Aug;10(8):465–76. [PMID: 2377459]
Burnier M et al. Measuring, analyzing, and managing drug adherence in resistant hypertension. Hypertension. 2013 Aug;62(2):218–25. [PMID: 23753412]
Laurent S et al. New drugs, procedures, and devices for hypertension. Lancet. 2012 Aug 11;380(9841):591–600. [PMID: 22883508]
Solini A et al. How can resistant hypertension be identified and prevented? Nat Rev Cardiol. 2013 May;10(5):293–6. [PMID: 23459606]
HYPERTENSIVE URGENCIES & EMERGENCIES
Hypertensive emergencies have become less frequent in recent years but still require prompt recognition and aggressive but careful management. A spectrum of urgent presentations exists, and the appropriate therapeutic approach varies accordingly.
Hypertensive urgencies are situations in which blood pressure must be reduced within a few hours. These include patients with asymptomatic severe hypertension (systolic blood pressure > 220 mm Hg or diastolic pressure > 125 mm Hg that persists after a period of observation) and those with optic disk edema progressive target organ complications, and severe perioperative hypertension. Elevated blood pressure levels alone—in the absence of symptoms or new or progressive target organ damage—rarely require emergency therapy. Parenteral drug therapy is not usually required, and partial reduction of blood pressure with relief of symptoms is the goal.
Hypertensive emergencies require substantial reduction of blood pressure within 1 hour to avoid the risk of serious morbidity or death. Although blood pressure is usually strikingly elevated (diastolic pressure > 130 mm Hg), the correlation between pressure and end-organ damage is often poor. It is the latter that determines the seriousness of the emergency and the approach to treatment. Emergencies include hypertensive encephalopathy (headache, irritability, confusion, and altered mental status due to cerebrovascular spasm), hypertensive nephropathy (hematuria, proteinuria, and progressive kidney dysfunction due to arteriolar necrosis and intimal hyperplasia of the interlobular arteries), intracranial hemorrhage, aortic dissection, preeclampsia-eclampsia, pulmonary edema, unstable angina, or myocardial infarction. Malignant hypertension is by historical definition characterized by encephalopathy or nephropathy with accompanying hypertensive retinopathy. Progressive kidney disease usually ensues if treatment is not provided. The therapeutic approach is identical to that used with other antihypertensive emergencies.
Parenteral therapy is indicated in most hypertensive emergencies, especially if encephalopathy is present. The initial goal in hypertensive emergencies is to reduce the pressure by no more than 25% (within minutes to 1 or 2 hours) and then toward a level of 160/100 mm Hg within 2–6 hours. Excessive reductions in pressure may precipitate coronary, cerebral, or renal ischemia. To avoid such declines, the use of agents that have a predictable, dose-dependent, transient, and progressive antihypertensive effect is preferable. In that regard, the use of sublingual or oral fast-acting nifedipine preparations is best avoided.
Acute ischemic stroke is often associated with marked elevation of blood pressure, which will usually fall spontaneously. In such cases, antihypertensives should only be used if the systolic blood pressure exceeds 180–200 mm Hg, and blood pressure should be reduced cautiously by 10–15%. If thrombolytics are to be given, blood pressure should be maintained at < 185/110 mm Hg during treatment and for 24 hours following treatment.
In hemorrhagic stroke, the aim is to minimize bleeding with a target mean arterial pressure of < 130 mm Hg. In acute subarachnoid hemorrhage, as long as the bleeding source remains uncorrected, a compromise must be struck between preventing further bleeding and maintaining cerebral perfusion in the face of cerebral vasospasm. In this situation, blood pressure goals depend on the patient’s usual blood pressure. In normotensive patients, the target should be a systolic blood pressure of 110–120 mm Hg; in hypertensive patients, blood pressure should be treated to 20% below baseline pressure. In the treatment of hypertensive emergencies complicated by (or precipitated by) central nervous system injury, labetalol or nicardipine are good choices, since they are nonsedating and do not appear to cause significant increases in cerebral blood flow or intracranial pressure in this setting. In hypertensive emergencies arising from catecholaminergic mechanisms, such as pheochromocytoma or cocaine use, beta-blockers can worsen the hypertension because of unopposed peripheral vasoconstriction; nicardipine, clevidipine, or phentolamine are better choices. Labetalol is useful in these patients if the heart rate must be controlled. Table 11–12 summarizes treatment recommendations in hypertensive emergency.
Table 11–12. Treatment of hypertensive emergency depending on primary site of end-organ damage.
A growing number of agents are available for management of acute hypertensive problems. (Table 11–13 lists drugs, dosages, and adverse effects.)
Table 11–13. Drugs for hypertensive emergencies and urgencies in descending order of preference.
Sodium nitroprusside is no longer the treatment of choice; in most situations, appropriate control of blood pressure is best achieved using combinations of nicardipine or clevidipine plus labetalol or esmolol.
Patients with less severe acute hypertensive syndromes can often be treated with oral therapy. Suitable drugs will reduce the blood pressure over a period of hours. In those presenting as a consequence of noncompliance, it is usually sufficient to restore the patient’s previously established oral regimen.
When the blood pressure has been brought under control, combinations of oral antihypertensive agents can be added as parenteral drugs are tapered off over a period of 2–3 days.
Marik PE et al. Hypertensive emergencies: an update. Curr Opin Crit Care. 2011 Dec;17(6):569–80. [PMID: 21986463]
van den Born BJ et al. Dutch guideline for the management of hypertensive crisis—2010 revision. Neth J Med. 2011 May;69(5):248–55. [PMID: 21646675]